Main-group metal-based asymmetric catalysts and applications thereof

ABSTRACT

The present invention relates to a method and catalysts for the stereoselective addition of a nucleophile to a reactive π-bond of a substrate. The chiral, non-racemic catalysts of the present invention constitute the first examples of catalysts for nucleophilic additions that comprise a main-group metal and a tri- or tetra-dentate ligand.

GOVERNMENT FUNDING

Work described herein was supported in part with funding from theNational Institutes of Health. The United States Government has certainrights in this invention.

BACKGROUND OF THE INVENTION

The demand for enantiomerically pure compounds has grown rapidly inrecent years. One important use for such chiral, non-racemic compoundsis as intermediates for synthesis in the pharmaceutical industry. Forinstance, it has become increasingly clear that enantiomerically puredrugs have many advantages over racemic drug mixtures. These advantages(reviewed in, e.g., Stinson, S. C., Chem Eng News, Sep. 28, 1992, pp.46-79) include fewer side effects and greater potency ofenantiomerically pure compounds.

Traditional methods of organic synthesis have often been optimized forthe production of racemic materials. The production of enantiomericallypure material has historically been achieved in one of two ways: the useof enantiomerically pure starting materials derived from natural sources(the so-called “chiral pool”); or the resolution of racemic mixtures byclassical techniques. Each of these methods has serious drawbacks,however. The chiral pool is limited to compounds found in nature, soonly certain structures and configurations are readily available.Resolution of racemates often requires the use of resolving agents; thisprocess may be inconvenient and is certain to be time-consuming.Furthermore, resolution often means that the undesired enantiomer isdiscarded, thereby wasting half of the material.

SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a process forenantioselective chemical synthesis which generally comprises theaddition of a nucleophile to a π-bond in the presence of a non-racemicchiral catalyst to produce a enantiomerically enriched product. Theπ-bond containing substrate comprises a carbon-carbon orcarbon-heteroatom π-bond, the nucleophile is typically the conjugatebase of a weak acid, and the chiral catalyst comprises an asymmetrictetradentate or tridentate ligand complexed with a main-group metal ion.In the instance of the tetradentate ligand, the catalyst complex has arectangular planar or rectangular pyramidal geometry. The tridentateligand-metal complex assumes a planar or trigonal pyramidal geometry. Ina preferred embodiment, the ligand has at least one Schiff base nitrogencomplexed with the metal at the core of the catalyst. In anotherpreferred embodiment, the ligand provides at least one stereogeniccenter within two bonds of a ligand atom which coordinates the metal.

In general, the metal atom is a main-group metal from Groups 1, 2, 12,13, or 14 and may be in its highest state of oxidation. In preferredembodiments, the metal atom is selected from the group comprising Li,Be, Na, Mg, K, Ca, B, Al, Ga, In, Zn, Cd, Hg, Si, Ge, and Sn. In highlypreferred embodiments, the metal is Al.

Exemplary substrates for the subject asymmetric nucleophilic additionreaction include aldehydes, enals, ketones, enones, enoates,α,β-unsaturated imides, imines, oximes, and hydrazones.

In preferred embodiments, the subject transformation can be representedby the conversion of 1 to 2, wherein the asterisk in 2 indicates anasymmetric center.

wherein

-   -   R, R′, and R″ represent, independently for each occurrence,        hydrogen, alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio,        imine, amide, phosphoryl, phosphonate, phosphine, carbonyl,        carboxyl, carboxamide, anhydride, silyl, thioalkyl,        alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde,        ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl,        aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime,        sulfonamide, thioamide, thiocarbamate, urea, thiourea, or        —(CH₂)_(m)—R₈₀;    -   X is selected from the group comprising CR₂, O, S, Se, and NR″;    -   Y is selected, independently for each occurrence, from the set        comprising H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, SiR₃ and        SnR₃; and

Nu is selected from the set comprising conjugate bases of weak Bronstedacids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide,thioalkoxide, carboxylate, thiocarboxylate—and carbanions;

-   -   R₈₀ represents an unsubstituted or substituted aryl, a        cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and    -   m is an integer in the range 0 to 8 inclusive.

In a preferred embodiment, the method includes combining a substratethat comprises a reactive π-bond, a nucleophile, and a non-racemicchiral catalyst as described herein, and maintaining the combinationunder conditions appropriate for the chiral catalyst to catalyze astereoselective addition of the nucleophile to a reactive π-bond of thesubstrate.

In preferred embodiments, the chiral catalyst which is employed in thesubject reaction is represented by the general formula:

in which

-   -   Z₁, Z₂, Z₃ and Z₄ each represent a Lewis base;    -   the C₁ moiety, taken with Z₁, Z₃ and M, and the C₂ moiety, taken        with Z₂, Z₄ and M, each, independently, form a heterocycle;    -   R₁, R₂, R′₁ and R′₂ each, independently, are absent or represent        a covalent substitution with an organic or inorganic substituent        permitted by valence requirements of the electron donor atom to        which it is attached,    -   R₄₀ and R₄₁ each independently are absent, or represent one or        more covalent substitutions of C₁ and C₂ with an organic or        inorganic substituent permitted by valence requirements of the        ring atom to which it is attached,    -   or any two or more of the R₁, R₂, R′₁, R′₂ R₄₀ and R₄₁ taken        together form a bridging substituent;    -   with the proviso that C₁ is substituted at at least one site by        R₁, R′₁ or R₄₁, and C₂ is substituted at at least one site by        R₂, R′₂ or R₄₀, and at least one of R₁, R′₁ and R₄₁ is taken        together with at least one of R₂, R′₂ and R₄₀ to form a bridging        substituent so as to provide Z₁, Z₂, Z₃ and Z₄ as a        tetradentate;    -   M represents the main-group metal ion; and    -   A represents a counterion or a nucleophile,        wherein each R₁, R₂, R′₁, R′₂ R₄₀ and R₄₁ are selected to        provide at least one stereogenic center in the tetradentate        ligand.

In exemplary embodiments, R₁, R₂, R′₁ and R′₂, independently, representhydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl,silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls,phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₈;

-   -   each R₄₀ and R₄₁ occuring in 100 independently represent        hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino,        nitro, thiol, amines, imines, amides, phosphoryls, phosphonates,        phosphines, carbonyls, carboxyls, silyls, ethers, thioethers,        sulfonyls, selenoethers, ketones, aldehydes, esters, or        —(CH₂)_(m)—R₈;    -   R₈ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle;    -   Z₁, Z₂, Z₃ and Z₄ are independently selected from the group        consisting of nitrogen, oxygen, phosphorus, arsenic, and sulfur;        and    -   m is zero or an integer in the range of 1 to 8.

For example, the catalyst can be represented by the general formula:

in which

-   -   the substituents R₁, R₂, Y₁, Y₂, X₁, X₂, X₃ and X₄ each,        independently, represent hydrogen, halogens, alkyls, alkenyls,        alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol,        amines, imines, amides, phosphoryls, phosphonates, phosphines,        carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,        selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₈,    -   or any two or more of the substituents taken together form a        carbocyle or heterocycle ring having from 4 to 8 atoms in the        ring structure,    -   with the proviso that at least one of R₁, Y₁, X₁ and X₂ is        covalently bonded to at least one of R₂, Y₂, X₃ and X₄ to        provide the β-iminocarbonyls to which they are attached as a        tetradentate ligand, and at least one of Y₁ and Y₂ is a        hydrogen;    -   R₈ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle, or a polycycle;    -   m is zero or an integer in the range of 1 to 8;    -   M represents the main-group metal; and    -   A represents a counterion or a nucleophile,        wherein each of of the substituents R₁, R₂, Y₁, Y₂, X₁, X₂, X₃        and X₄, are selected such that the catalyst is asymmetric.

For example, a preferred class of catalysts are represented by thegeneral formula:

in which

-   -   the B₁ moiety represents a diimine bridging substituent        represented by —R₁₅—R₁₆—R₁₇—, wherein R₁₅ and R₁₇ each        independently are absent or represent an alkyl, an alkenyl, or        an alkynyl, and R₁₆ is absent or represents an amine, an imine,        an amide, a phosphoryl, a carbonyl, a silyl, an oxygen, a        sulfur, a sufonyl, a selenium, a carbonyl, or an ester;    -   each of B₂ and B₃ independently represent rings selected from a        group consisting of cycloalkyls, cycloakenyls, aryls, and        heterocyclic rings, which rings comprising from 4 to 8 atoms in        a ring structure;    -   Y₁ and Y₂ each independently represent hydrogen, halogens,        alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino,        nitro, thiol, amines, imines, amides, phosphoryls, phosphonates,        phosphines, carbonyls, carboxyls, silyls, ethers, thioethers,        sulfonyls, selenoethers, ketones, aldehydes, esters, or        —(CH₂)_(m)—R₈,    -   R₁₂, R₁₃, and R₁₄ each independently are absent, or represent        one or more covalent substitutions of B₁, B₂ and B₃ with        halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro,        thiol, amines, imines, amides, phosphoryls, phosphonates,        phosphines, carbonyls, carboxyls, silyls, ethers, thioethers,        sulfonyls, selenoethers, ketones, aldehydes, esters, or        —(CH₂)_(m)—R₈, wherein R₁₂ can occur on one or more positions of        —R₁₅—R₁₆—R₁₇—,    -   or any two or more of the R₁₂, R₁₃, R₁₄, Y₁ and Y₂ taken        together form a bridging substituent;    -   R₈ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle, or a polycycle;    -   m is zero or an integer in the range of 1 to 8;    -   M represents a main-group metal; and    -   A represents a counterion or a nucleophile,        wherein R₁₂, R₁₃, R₁₄, Y and Y₂ are selected such that the        catalyst is asymmetric.

In yet further preferred embodiments, the catalyst is a metallosalenatecatalyst represented by the general formula:

in which

-   -   each of the substituents R₁, R₂, R₃, R₄, R₅, Y, Y₂, X₁, X₂, X₃,        X₄, X₆, X₇, and X₈, independently, represent hydrogen, halogens,        alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino,        nitro, thiol, amines, imines, amides, phosphoryls, phosphonates,        phosphines, carbonyls, carboxyls, silyls, ethers, thioethers,        sulfonyls, selenoethers, ketones, aldehydes, esters, or        —(CH₂)_(m)—R₈;    -   or any two or more of the substituents taken together form a        carbocycle or heterocycle having from 4 to 10 atoms in the ring        structure;    -   R₈ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle;    -   m is zero or an integer in the range of 1 to 8;    -   M represents a main-group metal; and    -   A represents a counterion or a nucleophile;        wherein if R₅ is absent, at least one of R₁ and R₂ is taken        together with at least one of R₃ and R₄ to form a bridging        substituent, and each of of the substituents of 106 are selected        such that the salenate is asymmetric.

Alternatively, the catalyst can have a tridentate ligand, such as theligand represented by the general formula:

in which

-   -   Z₁, Z₂, and Z₃ each represent a Lewis base;    -   the E₁ moiety, taken with Z₁, Z₂ and M, and the E₂ moiety, taken        with Z₂, Z₃ and M, each, independently, form a heterocycle;    -   R₈₀ and R₈₁ each independently are absent, hydrogen, halogens,        alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino,        nitro, thiolamines, imines, amides, phosphonates, phosphines,        carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,        selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₈, or        any two or more of the R₈₀ and R₈₁ substituents taken together        form a bridging substituent;    -   R₈ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle;    -   m is zero or an integer in the range of 1 to 8;    -   M represents a main-group metal; and    -   A represents a counteranion or a nucleophile; and    -   wherein the tridentate ligand is asymmetric.

DETAILED DESCRIPTION OF THE INVENTION

The demand for enantiomerically pure compounds has grown rapidly inrecent years. One important use for such chiral, non-racemic compoundsis as intermediates for synthesis in the pharmaceutical industry. Forinstance, it has become increasingly clear that enantiomerically puredrugs have many advantages over racemic drug mixtures. These advantages(reviewed in, e.g., Stinson, S. C., Chem Eng News, Sep. 28, 1992, pp.46-79) include fewer side effects and greater potency ofenantiomerically pure compounds. As described herein, the presentinvention makes available methods and reagents for enantioselectivesynthesis involving nucleophilic addition reactions. The primaryconstituents of the method, set out in more detail below, are a chiral,non-racemic metal catalyst of particular tetradentate or tridentategeometry; a chiral or prochiral carbon-carbon or carbon-heteroatomπ-bond, and a nucleophile—typically a weak acid or its conjugate base;the substrate containing the reactive π-bond, and the nucleophile arechosen so that the outcome of the reaction is influenced by the presenceof the aforementioned chiral, non-racemic catalyst.

I. Definitions

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

The term “nucleophile” is recognized in the art, and as used hereinmeans a chemical moiety having a reactive pair of electrons. Examples ofnucleophiles include uncharged compounds such as amines, mercaptans andalcohols, and charged moieties such as alkoxides, thiolates, carbanions,and a variety of organic and inorganic anions. Illustrative anionicnucleophiles include simple anions such as azide, cyanide, thiocyanate,acetate, formate or chloroformate, and bisulfite. Organometallicreagents such as organocuprates, organozincs, organolithiums, Grignardreagents, enolates, acetylides, and the like may, under approriatereaction conditions, be suitable nucleophiles. Hydride may also be asuitable nucleophile when reduction of the substrate is desired.

The term “electrophile” is art-recognized and refers to chemicalmoieties which can accept a pair of electrons from a nucleophile asdefined above. Electrophiles useful in the method of the presentinvention include cyclic compounds such as epoxides, aziridines,episulfides, cyclic sulfates, carbonates, lactones, lactams and thelike. Non-cyclic electrophiles include sulfates, sulfonates (e.g.tosylates), chlorides, bromides, iodides, and the like.

The terms “electrophilic atom”, “electrophilic center” and “reactivecenter” as used herein refer to the atom of the substrate which isattacked by, and forms a new bond to, the nucleophile. In most (but notall) cases, this will also be the atom from which the leaving groupdeparts.

The terms “Lewis base” and “Lewis basic” are recognized in the art, andrefer to a chemical moiety capable of donating a pair of electrons undercertain reaction conditions. Examples of Lewis basic moieties includeuncharged compounds such as alcohols, thiols, olefins, and amines, andcharged moieties such as alkoxides, thiolates, carbanions, and a varietyof other organic anions.

The terms “Lewis acid” and “Lewis acidic” are art-recognized and referto chemical moieties which can accept a pair of electrons from a Lewisbase as defined above.

The term “electron-withdrawing group” is recognized in the art and asused herein means a functionality which draws electrons to itself morethan a hydrogen atom would at the same position. Exemplaryelectron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl,trifluoromethyl, —CN, chloride, and the like. The term“electron-donating group”, as used herein, means a functionality whichdraws electrons to itself less than a hydrogen atom would at the sameposition. Exemplary electron-donating groups include amino, methoxy, andthe like.

The term, “chelating agent” refers to an organic molecule havingunshared electron pairs available for donation to a metal ion. The metalion is in this way coordinated by the chelating agent.

The terms, “bidentate chelating agent”, “tridentate chelating agent”,and “tetradentate chelating agent” refer to chelating agents having,respectively, two, three, and four electron pairs readily available forsimultaneous donation to a metal ion coordinated by the chelating agent.

The term “catalyst” refers to a substance the presence of whichincreases the rate of a chemical reaction, while not being consumed orundergoing a permanent chemical change itself.

The terms, “bidentate catalyst”, “tridentate catalyst”, and“tetradentate catalyst” refer to catalysts having, respectively, two,three, and four contact points with the substrate of the catalyst.

The term “coordination” refers to an interaction in which an electronpair donor coordinatively bonds (is “coordinated”) to one metal ion.

The term “coordinate bond” refers to an interaction between an electronpair donor and a coordination site on a metal ion leading to anattractive force between the electron pair donor and the metal ion.

The term “coordination site” refers to a point on a metal ion that canaccept an electron pair donated, for example, by a chelating agent.

The term “free coordination site” refers to a coordination site on ametal ion that is occupied by a water molecule or other species that isweakly donating relative to a polyamino acid tag, such as a histidinetag.

The term “coordination number” refers to the number of coordinationsites on a metal ion that are available for accepting an electron pair.

The term “complex” as used herein and in the claims means a coordinationcompound formed by the union of one or more electron-rich andelectron-poor molecules or atoms capable of independent existence withone or more electronically poor molecules or atoms, each of which isalso capable of independent existence.

The term “ring expansion” refers to a process whereby the number ofatoms in a ring of a cyclic compound is increased. An illustrativeexample of ring expansion is the reaction of epoxides with carbondioxide to yield cyclic carbonates.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

The term “meso compound” is recognized in the art and means a chemicalcompound which has at least two chiral centers but is achiral due to thepresence of an internal plane or point of symmetry.

The term “chiral” refers to molecules which have the property ofnon-superimposability of their mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. A “prochiral molecule” is a molecule which has thepotential to be converted to a chiral molecule in a particular process.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space. In particular, “enantiomers” refer to twostereoisomers of a compound which are non-superimposable mirror imagesof one another. “Diastereomers”, on the other hand, refers tostereoisomers with two or more centers of dissymmetry and whosemolecules are not mirror images of one another.

Furthermore, a “stereoselective process” is one which produces aparticular stereoisomer of a reaction product in preference to otherpossible stereoisomers of that product. An “enantioselective process” isone which favors production of one of the two possible enantiomers of areaction product. The subject method is said to produce a“stereoisomerically-enriched” product (e.g., enantiomerically-enrichedor diastereomerically-enriched) when the yield of a particularstereoisomer of the product is greater by a statistically significantamount relative to the yield of that stereoisomer resulting from thesame reaction run in the absence of a chiral catalyst. For example, areaction which routinely produces a racemic mixture will, when catalyzedby one of the subject chiral catalysts, yield an e.e. for a particularenantiomer of the product.

The term “regioisomers” refers to compounds which have the samemolecular formula but differ in the connectivity of the atoms.Accordingly, a “regioselective process” is one which favors theproduction of a particular regioisomer over others, e.g., the reactionproduces a statistically significant majority of a certain regioisomer.

The term “reaction product” means a compound which results from thereaction of the two substrate molecules. In general, the term “reactionproduct” will be used herein to refer to a stable, isolable compound,and not to unstable intermediates or transition states.

The term “complex” as used herein and in the claims means a coordinationcompound formed by the union of one or more electronically richmolecules or atoms capable of independent existence with one or moreelectronically poor molecules or atoms, each of which is also capable ofindependent existence.

The term “substrate” is intended to mean a chemical compound which canreact under the subject conditions to yield a product having at leastone stereogenic center.

The term “catalytic amount” is recognized in the art and means asubstoichiometric amount of the catalyst relative to a reactant. As usedherein, a catalytic amount means from 0.0001 to 90 mole percent catalystrelative to a reactant, more preferably from 0.001 to 50 mole percent,still more preferably from 0.01 to 10 mole percent, and even morepreferably from 0.1 to 5 mole percent catalyst to reactant.

As discussed more fully below, the reactions contemplated in the presentinvention include reactions which are enantioselective,diastereoselective, and/or regioselective. An enantioselective reactionis a reaction which converts an achiral reactant to a chiral productenriched in one enantiomer. Enantioselectivity is generally quantifiedas “enantiomeric excess” (ee) defined as follows: $\begin{matrix}{\%\quad{enantiomeric}} \\{{excess}\quad{A({ee})}}\end{matrix} = {\left( {\%\quad{enantiomer}\quad A} \right) - \left( {\%\quad{enantiomer}\quad B} \right)}$where A and B are the enantiomers formed. Additional terms that are usedin conjunction with enatioselectivity include “optical purity” or“optical activity”. An enantioselective reaction yields a product withan e.e. greater than zero. Preferred enantioselective reactions yield aproduct with an e.e. greater than 20%, more preferably greater than 50%,even more preferably greater than 70%, and most preferably greater than80%.

A diastereoselective reaction converts a reactant or reactants (whichmay be achiral, racemic, non-racemic or enantiomerically pure) to aproduct enriched in one diastereomer. If the chiral reactant is racemic,in the presence of a chiral, non-racemic reagent or catalyst, onereactant enantiomer may react more slowly than the other. This effect istermed a kinetic resolution, wherein the reactant enantiomers areresolved by differential reaction rate to yield an enantiomericallyenriched product. Kinetic resolution is usually achieved by the use ofsufficient reagent to react with only one reactant enantiomer (i.e.one-half mole of reagent per mole of racemic substrate). Examples ofcatalytic reactions which have been used for kinetic resolution ofracemic reactants include the Sharpless epoxidation and the Noyorihydrogenation.

A regioselective reaction is a reaction which occurs preferentially atone reactive center rather than another reactive center. For example, aregioselective cycloaddition reaction of an unsymmetrical 1,3,5-trienesubstrate would preferentially occur at one of the two 1,3-dienescontained therein.

The term “non-racemic” means a preparation having greater than 50% of adesired stereoisomer, more preferably at least 75%. “Substantiallynon-racemic” refers to preparations which have greater than 90% ee for adesired stereoisomer, more preferably greater than 95% ee.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branchedchain), and more preferably 20 of fewer. Likewise, preferred cycloalkylshave from 4-10 carbon atoms in their ring structure, and more preferablyhave 5, 6 or 7 carbons in the ring structure.

Moreover, the term alkyl as used throughout the specification and claimsis intended to include both “unsubstituted alkyls” and “substitutedalkyls”, the latter of which refers to alkyl moieties havingsubstituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, ahalogen, a hydroxyl, an alkoxyl, a silyloxy, a carbonyl, and ester, aphosphoryl, an amine, an amide, an imine, a thiol, a thioether, athioester, a sulfonyl, an amino, a nitro, or an organometallic moiety.It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude substituted and unsubstituted forms of amines, imines, amides,phosphoryls (inlcuding phosphonates and phosphines), sulfonyls(inlcuding sulfates and sulfonates), and silyl groups, as well asethers, thioethers, selenoethers, carbonyls (including ketones,aldehydes, carboxylates, and esters), —CF₃, —CN and the like. Exemplarysubstitued alkyls are described below. Cycloalkyls can be furthersubstituted with alkyls, alkenyls, alkoxys, thioalkyls, aminoalkyls,carbonyl-substituted alkyls, CF₃, CN, and the like.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but which contain at least one double or triple bond,respectively.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths.

As used herein, the term “amino” means —NH₂; the term “nitro” means—NO₂; the term “halogen” designates —F, —Cl, —Br or —I; the term “thiol”means —SH; the term “hydroxyl” means —OH; the term “sulfonyl” means—SO₂—; and the term “organometallic” refers to a metallic atom (such asmercury, zinc, lead, magnesium or lithium) or a metalloid (such assilicon, arsenic or selenium) which is bonded directly to a carbon atom,such as a diphenylmethylsilyl group.

Thus, the term “alkylamine” as used herein means an alkyl group, asdefined above, having a substituted or unsubstituted amine attachedthereto. In exemplary embodiments, an “amine” can be represented by thegeneral formula:

wherein R₈ and R₉ each independently represent a hydrogen, an alkyl, analkenyl, —(CH₂)_(m)—R₇, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl,—C(═O)—(CH₂)_(m)—R₇, or R₈ and R₉ taken together with the N atom towhich they are attached complete a heterocycle having from 4 to 8 atomsin the ring structure; R₇ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8.

Likewise, the term “alkylamide” refers to an alkyl group having asubstituted or unsubstituted amide group attached thereto. For instance,an “amide” can be represented by the general formula:

wherein R₈ and R₉ are as defined above.

The term “alkylimine” refers to an alkyl group having a substituted orunsubstituted imine attached thereto. An “imine” can be represented bythe general formula:

wherein R₈ is as described above.

The term “thioalkyl” refers to an alkyl group, as defined above, havinga sulfhydryl or thioether group attached thereto. In preferredembodiments, the “thioether” moiety is represented by one of —S-alkyl,—S-alkenyl, —S-alkynyl, and —S—(CH₂)_(m)—R₇, wherein m and R₇ aredefined above.

The term “carbonyl-substituted alkyl” as used herein means an alkylgroup, as defined above, having a substituted or unsubstituted carbonylgroup attached thereto, and includes aldehydes, ketones, carboxylatesand esters. In exemplary embodiments, the “carbonyl” moiety isrepresented by the general formula:

wherein X is absent or represents an oxygen or a sulfur, and R₁₀represents a hydrogen, an alkyl, an alkenyl, or —(CH₂)_(m)—R₇, where mand R₇ are as defined above. Where X is an oxygen, the formularepresents an “ester”. Where X is a sulfur, the formula represents a“thioester.” Where X is absent, and R₁₀ is not hydrogen, the aboveformula represents a “ketone” group. Where the oxygen atom of the aboveformula is replaced by sulfur, the formula represents a “thiocarbonyl”group.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propoxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl whichrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R₇,where m and R₇ are described above.

Thus, the term “phosphorylalkyl” as used herein means an alkyl group, asdefined above, having a substituted or unsubstituted phosphoryl groupattached thereto. A “phosphoryl” can in general be represented by theformula:

wherein Q₁ represented S or O, and R₄₆ represents hydrogen, a loweralkyl or an aryl. When used to substitute an alkyl, the phosphoryl groupof the phosphorylalkyl can be represented by the general formula:

wherein Q₁ represented S or O, and each R₄₆ indepedently representshydrogen, a lower alkyl or an aryl, Q₂ represents O, S or N.

The term “metalloalkyl” refers to an alkyl group, as defined above,having a substituted or unsubstituted organometallic group attachedthereto. A “silyl alkyl” is an alkyl having a substituted siliconattached thereto. In a preferred embodiment, the “silyl” moiety whichmay be substituted on the alkyl can be represented by the generalformula:

wherein R₁₀, R′₁₀ and R″¹⁰ independently represent a hydrogen, an alkyl,an alkenyl, or —(CH₂)_(m)—R₇, m and R₇ being defined above.

Likewise, a “selenoalkyl” refers to an alkyl group having a substitutedseleno group attached thereto. Exemplary “selenoethers” which may besubstituted on the alkyl are selected from one of —Se-alkyl,—Se-alkenyl, —Se-alkynyl, and —Se—(CH₂)_(m)—R₇, m and R₇ being definedabove.

The term “sulfonyl” as used herein means a S(O)₂ moiety bonded to twocarbon atoms. Thus, in a preferred embodiment, a sulfonate has thefollowing structure:

wherein the single bonds are between carbon and sulfur.

The term “sulfonate” as used herein means a sulfonyl group, as definedabove, attached to a hydroxyl, alkyloxy or aryloxy group. Thus, in apreferred embodiment, a sulfonate has the structure:

in which R′₁ is absent, hydrogen, alkyl, or aryl.

The term “sulfate”, as used herein, means a sulfonyl group, as definedabove, attached to two hydroxy or alkoxy groups. Thus, in a preferredembodiment, a sulfate has the structure:

in which R₄₀ and R₄₁ are independently absent, a hydrogen, an alkyl, oran aryl. Furthermore, R₄₀ and R₄₁, taken together with the sulfonylgroup and the oxygen atoms to which they are attached, may form a ringstructure having from 5 to 10 members.

Analogous substitutions can be made to alkenyl and alkynyl groups toproduce, for example, alkenylamines, alkynylamines, alkenylamides,alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls,metalloalkenyls and metalloalkynyls.

The term “aryl” as used herein includes 4-, 5-, 6- and 7-memberedsingle-ring aromatic groups which may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazineand pyrimidine, and the like. Those aryl groups having heteroatoms inthe ring structure may also be referred to as “aryl heterocycle”. Thearomatic ring can be substituted at one or more ring positions with suchsubstituents as described above, as for example, halogens, alkyls,alkenyls, alkynyls, hydroxyl, amino, nitro, thiolamines, imines, amides,phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₇, —CF₃, —CN, or the like.

The terms “heterocycle” or “heterocyclic group” refer to 4 to10-membered ring structures, more preferably 5 to 7 membered rings,which ring structures include one to four heteroatoms. Heterocyclicgroups include pyrrolidine, oxolane, thiolane, imidazole, oxazole,piperidine, piperazine, morpholine. The heterocyclic ring can besubstituted at one or more positions with such substituents as describedabove, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl,amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines,carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇, —CF₃, —CN,or the like.

The terms “polycycle” or “polycyclic group” refer to two or more cyclicrings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocycles) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl,silyloxy, amino, nitro, thiol, amines, imines, amides, phosphonates,phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇, —CF₃, —CN,or the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur, phosphorus and selenium.

A “bridging substituent” refers to a substitution at two (or more) siteson the core structure of the catalyst by the same (as opposed toidentical) substituent so as to form a covalent bridge between thesubstitution sites. For example, a bridging substituent may berepresented by the general formula or —R₁₅—R₁₆—R₁₇—, wherein R₁₅ and R₁₇each independently are absent or represent an alkyl, an alkenyl, or analkynyl, preferably C₁ to C₁₀, and R₁₆ is absent or represents an amine,an imine, an amide, a phosphoryl a carbonyl, a silyl, an oxygen, asulfonyl, a sulfer, a selenium, or an ester. Exemplary bridgingsubstituents are given by the “picnic basket” forms of, for instance,the porphoryn catalysts described below.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Alsofor purposes of this invention, the term “hydrocarbon” is contemplatedto include all permissible compounds having at least one hydrogen andone carbon atom. In a broad aspect, the permissible hydrocarbons includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic organic compounds which can besubstituted or unsubstituted.

The term “amino acid” is intended to embrace all compounds, whethernatural or synthetic, which include both an amino functionality and anacid functionality, including amino acid analogs and derivatives. Alsoincluded in the term “amino acid” are amino acid mimetics such asβ-cyanoalanine, norleucine, 3-phosphoserine, homoserine,dihydroxyphenylalanine, 5-hydroxytryptophan, and the like.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described hereinabove. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalencies of the heteroatoms. This invention is not intended to belimited in any manner by the permissible substituents of organiccompounds.

II. Catalyzed Reactions

In one aspect of the present invention there is provided a process forstereoselectively producing compounds with at least one stereogeniccenter. An advantage of this invention is that enantiomerically enrichedproducts can be synthesized from achiral or racemic reactants. Anotheradvantage is that yield loses associated with the production of anundesired enantiomer can be substantially reduced.

In general, the invention features a stereoselective nucleophilicaddition process which comprises combining a substrate comprising areactive π-bond, a nucleophile, and at least a catalytic amount of anon-racemic, chiral catalyst of particular characteristics (as describedbelow). The combination is maintained under conditions appropriate forthe chiral catalyst to catalyze stereoselective addition of thenucleophile to a reactive π-bond of the substrate. This reaction can beapplied to enatioselective processes as well as diastereoselectiveprocesses. It may also be adapted for regioselective reactions. Examplesof enantioselective reactions, kinetic resolution, and regioselectivereactions which may be catalyzed according to the present inventionfollow.

In an exemplary embodiment, cyanide ion adds to the carbon of an iminefunctional group in the presence of a subject chiral, non-racemiccatalyst yielding a non-racemic α-amino nitrile product. This embodimentis an example of a subject enantioselective nucleophilic additionreaction. The product of this reaction can be transformed in a singlestep to non-racemic N-methyl phenylglycine—a non-natural α-amino acid.

In another aspect of the invention, the nucleophilic addition reactionoccurs in a diastereoselective manner in the presence of a chiral,non-racemic catalyst. An illustrative example of a diastereoselectivereaction of the present invention is shown below.

In another illustrative embodiment, the present invention provides amethod for the kinetic resolution of a racemic mixture of an iminecontaining an α-stereocenter. In the subject catalyst-mediated kineticresolution process involving a racemic imine substrate, one enantiomerof the imine can be recovered as unreacted substrate while the other istransformed to the desired product. This aspect of the inventionprovides methods of synthesizing functionalized non-racemic productsfrom racemic starting materials. This embodiment is a diastereoselectiveprocess as well.

A second type of kinetic resolution possible with the subject methodinvolves the resolution of a racemic nucleophile. The exemplaryembodiment shown below centers on the resolution of a racemic mixture ofthiols in catalyzed reaction with O-methyl benzophenone oxime. Use ofapproximately 0.5 equivalents of the oxime ether in the subject methodwill provide a product mixture comprising both non-racemic unreactedthiol and a non-racemic addition product.

Skilled artisans will recognize that the subject invention can beapplied to substrates comprising two reactive π-bonds of differingreactivity. The illustrative embodiment below involves a diiminesubstrate wherein the imines differ in their steric environments; thesubject method is expected, all other factors being equal, to catalyzeselectively nucleophilic addition at the less hindered imine moiety.

Additionally, skilled artisans will recognize that the subject inventioncan be applied to substrates comprising different classes of reactiveπ-bonds. The illustrative embodiment below involves a substrate thatcomprises both an imine and a hydrazone. The subject method is expected,all other factors being equal, to catalyze nucleophilic addition at theimine moiety.

The subject method and catalysts may also be exploited in anintramolecular sense. In the illustrative embodiment that follows, thechiral, non-racemic catalyst catalyzes the intramolecularenantioselective addition of a thiol to an N-allyl imine.

The processes of this invention can provide optically active productswith very high stereoselectivity (e.g., enantioselectivity ordiasteroselectivity) or regioselectivity. In preferred embodiments ofthe subject enantioselective reactions, enantiomeric excesses ofpreferably greater than 50%, more preferably greater than 75% and mostpreferably greater than 90% can be obtained by the processes of thisinvention. Likewise, with respect to regioselective reactions, molarratios for desired/undesired regioisomers of preferably greater than5:1, more preferably greater than 10:1 and most preferably greater than25:1 can be obtained by the processes of this invention. The processesof this invention occur at reaction rates suitable for commercialexploitation.

As is clear from the above discussion, the chiral products produced bythe asymmetric synthesis processes of this invention can undergo furtherreaction(s) to afford desired derivatives thereof. Such permissiblederivatization reactions can be carried out in accordance withconventional procedures known in the art. For example, potentialderivatization reactions include epoxidation, ozonolysis, halogenation,hydrohalogenation, hydrogenation, esterification, oxidation of alcoholsto aldehydes, ketones and/or carboxylate derivatives, N-alkylation ofamides, addition of aldehydes to amides, nitrile reduction, acylation ofalcohols by esters, acylation of amines and the like. To furtherillustrate, exemplary classes of pharmaceuticals which can besynthesized by a scheme including the subject stereoselective reactionare cardiovascular drugs, nonsteroidal antiinflammatory drugs, centralnervous system agents, and antihistaminics.

III. Catalysts

The catalysts employed in the subject method involve chiral complexeswhich provide controlled steric environments for asymmetric nucleophilicaddition reactions. In general, catalysts intended by the presentinvention can be characterized in terms of a number of features. Forinstance, a salient aspect of each of the catalysts contemplated by theinstant invention concerns the use of metalloligands which provide arigid or semi-rigid environment near the catalytic site of the molecule.This feature, through imposition of structural rigidity on the chelatedmetal, can be used to establish selective approach of the substrate tothe catalytic site and thereby induce stereoselectivity and/orregioselectivity in a nucleophilic addition reaction. Moreover, theligand preferably places a restriction on the coordination sphere of themetal.

Another aspect of the catalyst concerns the selection of metal atoms forthe catalyst. In general, any main-group metal may be used to form thecatalyst, e.g., a metal selected from one of Groups 1, 2, 12, 13, or 14of the periodic table. However, in preferred embodiments, the metal willbe selected from Groups 12, 13, or 14. For example, suitable metalsinclude Li, Na, K, Rb, Be, Mg, Ca, Sr, Zn, Cd, Hg, B, Al, Ga, In, Si,Ge, and Sn. Particularly preferred metals are from groups 13 or 14,especially Al(III).

A. Chiral Tetradentate Catalysts

Consistent with these desirable features, one class of particularlypreferred chiral catalysts provide a chiral tetradentate ligand whichcoordinates a main-group metal in a substantially square planar orsquare pyramidal geometry, though some distortion to these geometries iscontemplated. Restated, these square geometries refer to tetradentateligands in which the Lewis basic atoms lie substantially in the sameplane, with the metal also in that plane (square planar), or above orbelow that plane (square pyramidal).

Preferred square tetradentate catalysts which may be employed in thesubject reactions can be represented by the general formula 100:

wherein Z₁, Z₂, Z₃ and Z₄ each represent a Lewis base, such as selectedfrom the group consisting of nitrogen (e.g., imines, amines and amides),oxygen, phosphorus (e.g., phosphines or phosphinites), arsenic (arsines)and sulfur.

The C₁ moiety (taken with Z₁, Z₃ and M) and the C₂ moiety, (taken withZ₂, Z₄ and M) each, independently, form a heterocyclic ring. It will beunderstood that while the C₁ and C₂ structures depicted in the aboveformula may not formally be covalently closed rings for lack of acovalent bond with the metal M, for purposes of this disclosure, thisand similar structures involving the metal catalyst atom M willnevertheless be referred to as heterocyclic rings, and substituentsthereof will be referenced relative to heterocycle nomenclature (e.g.,“fused rings” or “bridged rings”). In addition to substitutions at R₁,R₂, R′₁ and R′₂, the C₁ and C₂ rings can of course be substituted asappropriate at other ring positions, as illustrated by R₄₀ and R₄₁.Moreover, it will be appreciated that in certain embodiments two or moresubstituents of C₁ can be covalently bonded to each other to provide afused ring or bridged ring including the C₁ ring atoms. Similarstructures can be provided on the C₂ ring.

Accordingly, in the illustrated structure 100, R₁, R₂, R′₁ and R′₂ eachindependently are absent, or represent some substitution, as permittedby valence requirements, of the Lewis basic atoms, which substitutionmay be with hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl,alkoxyl, silyloxy, amino, nitro, thio amines, imines, amides,phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₇; R₄₀ and R₄₁ each independently are absent, or representone or more covalent substitutions of C₁ and C₂ with an organic orinorganic substituent permitted by valence requirements of the ring atomto which it is attached, or any two or more of the R₁, R₂, R′₁, R′₂ R₄₀and R₄₁ substituents taken together can form a bridging substituent;with the proviso that at least one of R₁, R′₁ and R₄₁ forms a bridgingsubstituent with at least one of R₂, R′₂ and R₄₀ in order to provide C₁and C₂ as a tetradentate; R₇ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle, and m is zero or an integerin the range of 1 to 8.

While the actual substituents of C₁ and C₂ can vary widely as necessaryfor a particular reaction scheme, one important proviso is that at leastone substituent of C₁ must form a covalent bond with at least onesubstituent of C₂ in order to provide a tetradentate ligand which formsa square complex with M. That is, the ligand is a bridged cycle orpolycycle which includes C₁ and C₂. Furthermore, in order for thecatalyst to be chiral, e.g., to be capable of catalyzing stereoselectivereactions, R₁, R₂, R′₁, R′₂ and other substituents of C₁ and C₂ areselected to provide at least one stereogenic center or an axis ofdissymmetry, e.g. such that the ligand is asymmetric.

In the general structure 100, M represents a main-group metal of Groups1, 2, 12, 13, or 14 of the periodic table. In the most preferredembodiments, M will be selected from the group of late main-groupmetals, e.g., from the Group 12, 13, or 14 metals. Even more preferably,M will be Al(III). Moreover, the metal can be coordinated with acounteranion or a nucleophile.

Exemplary catalysts of this class are comprised of ligands derived from,for example, salens, porphyrins, crown ethers, azacrown ethers, cyclams,phthalocyanines, and the like.

In a particularly preferred embodiment, the subject reactions use achiral catalyst having a metal ion complexed via an imine of a chiralligand, preferably a diimine bridge. Accordingly, such variants ofstructure 100 can be provided in embodiments wherein any one or more ofthe Lewis bases is an imine, with metallo-Schiff base forms of iminesbeing highly preferred.

To further illustrate, a tetradentate catalyst useful in the subjectmethod can be derived using chiral salen or salen-like ligands(hereinafter “salenates”). The asymmetric metallosalenate catalystsoffer a distinct advantage over many other chiral tetradentate catalyts,such as the metalloporphyrinates described infra, in that the salenateligand can have stereogenic centers located just two bond lengths awayfrom the metal. This proximity of the chiral centers to the reactivesite can yield a high degree of stereoselectivity.

As disclosed herein, salen complexes are highly effective catalysts forasymmetric nucleophilic addition reactions. This group of reactions isnotable not only for its high stereoselectivity—enantioselectivity,diastereoselecivity, etc.—and for the utility of its products, but alsofor its remarkable efficiency as a catalytic process.

Moreover, the synthesis of chiral salenates is well characterized in theart, with more than 150 different chiral metallosalenates having beenreported in the literature (see, for review, Collman et al. (1993)Science 261:1404-1411). These ligands are easily and inexpensivelysynthesized on large scale starting from readily available materials, asdescribed in Larrow et al., J Org Chem (1994) 59:1939-1942. Importantly,the general familiarity and ease of synthesis of metallosalenatespermits the substituents to be readily varied in a systematic fashion inorder to adjust the steric or electronic characteristics of the ligand.This feature makes possible the synthesis of ligands which are optimizedfor particular types of reaction or substrate. It has been found thatsuch steric and electronic “tuning” (described infra) of the catalystscan have significant effects on the yield and e.e. of products formed inasymmetric reactions. In particular, the use of bulky blockingsubstituents is desirable to achieve high product e.e. in the asymmetricnucleophilic additions. Furthermore, the stereogenic moiety can easilybe modified to improve enantioselectivity.

In general, the salenate ligands which are useful in the subject methodas chiral metallosalenate catalysts can be characterized as twosubstituted β-iminocarbonyls which are linked to form a tetradentateligand having at least one stereogenic center. In an exemplaryembodiment, a metallosalenate catalyst useful in the asymmetricnucleophilic addition processes of the present invention can berepresented by a metal complex with two substituted β-iminocarbonylshaving the general formula:

in which

-   -   the substituents R₁, R₂, Y₁, Y₂, X₁, X₂, X₃ and X₄ each,        independently, represent hydrogen, halogens, alkyls, alkenyls,        alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol,        amines, imines, amides, phosphonates, phosphines, carbonyls,        carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers,        ketones, aldehydes, esters, or —(CH₂)_(m)—R₇,        -   or any two or more of the substituents taken together form a            carbocycle or heterocycle having from 4 to 8 atoms in the            ring structure, which ring structure may be a fused ring, as            in the case of, for example, X₁ and X₂ forming a ring, or            which ring may be a bridging ring, as in the case of R₁ and            R₂, X₂ and X₄, or Y₁ and X₂ representing different ends of a            single substituent,        -   with the proviso that at least one of R₁, Y₁, X₁ and X₂ is            covalently bonded to at least one of R₂, Y₂, X₃ and X₄ to            provide the β-iminocarbonyls as a tetradentate ligand;    -   R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle, or a polycycle;    -   m is zero or an integer in the range of 1 to 8;    -   M represents a main-group metal; and    -   A represents a counterion or a nucleophile;        wherein each of of the substituents of the β-iminocarbonyls,        e.g., R₁, R₂, Y₁, Y₂, X₁, X₂, X₃ and X₄, are selected such that        the catalyst is asymmetric.

The choice of each of R₁, R₂, Y₁, Y₂, X₁, X₂, X₃ and X₄ is alsodependent on electronic and steric considerations, e.g., the tuning ofthe catalyst for a particular set of substrates, as well as the solventsystem in which the reaction is to be carried out.

The chirality of the salenate ligand may be the result of the presenceof one or more chiral atoms (e.g. carbon, sulfur, phosphorus, or otheratoms capable of chirality), or may be the result of an axis ofasymmetry due to restricted rotation, helicity, molecular knotting orchiral metal complexation. In preferred embodiments, the chiral ligandhas at least one chiral atom or axis of asymmetry due to restrictedrotation. Further guidance respecting the particular choice of thesubstituents is set out herein.

In preferred embodiments, the choice of R₁, R₂, X₁, X₂, X₃ and X₄ yielda class of chiral catalysts which are represented by the generalformula:

-   -   in which the B₁ moiety represents a diimine bridge, e.g. a        bridging substituent which links the imino nitrogens of each        β-iminocarbonyl, and preferably contains at least one chiral        center of the salen ligand. For example, B₁, taken together with        the metal-coordinating imines of the β-iminocarbonyl, can        represent the diimine of an alkyl, an alkenyl, an alkynyl, or        the diimine of —R₁₅—R₁₆—R₁₇—, wherein R₁₅ and R₁₇ each        independently are absent or represent an alkyl, an alkenyl, or        an alkynyl, and R₁₆ is absent or represents an amine, an imine,        an amide, a phosphonate, a phosphine, a carbonyl, a carboxyl, a        silyl, an oxygen, a sulfur, a sulfonyl, a selenium, or an ester;        each of B₂ and B₃ independently represent rings selected from a        group consisting of cycloalkyls, cycloalkenyls, aryls, and        heterocycles, which rings comprise from 4 to 8 atoms in a ring        structure. The substituents R₁₂, R₁₃ and R₁₄ each independently        are absent, or represent one or more covalent substitutions of        B₁, B₂ and B₃ with halogens, alkyls, alkenyls, alkynyls,        hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines,        imines, amides, phosphonates, phosphines, carbonyls, carboxyls,        silyls, ethers, thioethers, sulfonyls, selenoethers, ketones,        aldehydes, esters, or —(CH₂)_(m)—R₇ (the substituent R₁₂        occuring on one or more positions of —R₁₅—R₁₆—R₁₇—); R₇        represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle,        or a polycycle; m is zero or an integer in the range of 1 to 8.        Moreover, any two or more of the R₁₂, R₁₃, R₁₄, Y₁ and Y₂        substituted taken together can form bridging substituents to        bridge the two β-iminocarbonyls and/or bridge different portions        of the same β-iminocarbonyl. As above, in order to provide for a        chiral catalyst, the choice of B₂ and B₃ (including their        substituents) and/or the choice of substituents on B₁ (e.g., B₁        has a stereogenic center) is made to establish a chiral ligand.        A represents a nucleophile or counterion.

In particular, as described in the appended examples, the salenateligand can be derived from condensation of a substituted salicylaldehydewith a substituted diamine, preferably one stereoisomer of a chiraldiamine, and then reacted with a desired metal to form a salen(N,N′-bis(salicylideneamino)alkyl)metal complex. An exemplary reactionfor generating the salen ligand is based on Zhang and Jacobsen J OrgChem (1991) 56:2296-2298, and Jacobsen et al. PCT WO93/03838, andcomprises:

Utilizing this reaction scheme and others generally known in the art canprovide a class of salens represented by the general formula 106:

in which

-   -   each of the substituents R₁, R₂, R₃, R₄, R₅, Y₁, Y₂, X₁, X₂, X₃,        X₄, X₅, X₆, X₇, and X₈, independently, represent hydrogen,        halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl,        silyloxy, amino, nitro, thiol, amines, imines, amides,        phosphoryls, phosphonates, phosphines, carbonyls, carboxyls,        silyls, ethers, thioethers, sulfonyls, selenoethers, ketones,        aldehydes, esters, or —(CH₂)_(m)—R₇;        -   or any two or more of the substituents taken together form a            carbocyle or heterocycle having at least 4 atoms in the ring            structure;    -   R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle;    -   m is zero or an integer in the range of 1 to 8; and    -   M represents a main-group metal;        wherein    -   if R₅ is absent, at least one of R₁ and R₂ is covalently bonded        to at least one of R₃ and R₄; and the substituents of the        salenate ligand are selected such that the salenate has at least        one stereogenic center, e.g., is asymmetric. Moreover, the metal        can be coordinated with a counterion (as in the aged catalyst        described below).

With respect to generating a chiral ligand, it is important to note whenselecting particular substituents that the salenate ligand has apotential catalytic site on both “sides” of the catalyst, e.g., relativeto the plane of the four coordinating atoms of the ligand. Accordingly,when selecting the appropriate substituents for the β-iminocarbonyls inthe above embodiments, it is important that either (1) both sides of thecatalyst have stereogenic centers which effect identicalstereoselectivity, or (2) the side having a stereogenic center ofappropriate stereoselectivity is accessible while the other side has ablocking structure which substantially impairs approach to the metalatom on that side.

The first of these options is preferred. In other words, it is preferredto have at least one stereogenic center on each side of the salenateligand, each having the same absolute (R or S) configuration. Forexample, (R,R)-1,2-Diphenyl-1,2-bis(3-tert-butylsalicylideamino)ethane,described in Example 1, contains two stereogenic centers on the diiminebridge which give rise to identical stereoselective faces on each sideof the catalyst. This C₂-symmetric catalyst has the advantage of notbeing susceptible to “leakage” reactions because substrate approach,albeit constrained, may occur from either face without loss ofselectivity.

In contrast, control of the reactivity of a “mono-faced” catalyst can beaccomplished by sterically hindering substrate approach to the undesiredface. For instance, the salenate(R)-2-phenyl-1,2-bis(3-tert-butylsalicylideamino)ethane, e.g., formula106 wherein R₁, R₂ and R₃ are protons, and R₄ is a phenyl, has twonon-equivalent faces in terms of enantioselectivity. Accordingly,derivatizing the salenate ligand with a group which blocks access to the“free” face (e.g., the face having both a C1 and C2 proton of thediimine) can establish the ligand as a chiral catalyst with oneenantiotopic face. For instance, a “picnic basket” form of the ligandcan be generated wherein the phenyl moiety of the diimine bridge is onthe “frontside” of the catalyst, and X₄ and X₈ are covalently linked toform a bridge on the “backside” of the catalyst, which bridgesubstitution precludes access to the metal ion from the backside. Thoseskilled in the art will recognize other single- and double-sidedembodiments (see, for example, Collman et al. (1993) Science 261:1404).

The synthetic schemes for metallosalenates, or precursors thereof, whichmay be useful in the present method can be adapted from the literature.For example, see Zhang et al. (1990) J Am Chem Soc 112:2801; Zhang etal. (1991) J Org Chem 56:2296; Jacobsen et al. (1991) J Am Chem Soc113:7063; Jacobsen et al. (1991) J Am Chem Soc 113:6703; Lee et al.(1991) Tetrahedron Lett 32:5055; Jacobsen, E. N. In Catalytic AsymmetricSynthesis, Ojima, I., Ed., VCH: New York, 1993, chapter 4.2; E. N.Jacobsen PCT Publications WO81/14694 and WO93/03838; Larrow et al.(1994) J Am Chem Soc 116:12129; Larrow et al. (1994) J Org Chem 59:1939;Irie et al. (1990) Tetrahedron Lett 31:7345; Irie et al. (1991) Synlett265; Irie et al. (1991) Tetrahedron Lett 32:1056; Irie et al. (1991)Tetrahedron Asymmetry 2:481; Katsuki et al. U.S. Pat. No. 5,352,814;Collman et al. (1993) Science 261:1404; Sasaki et al. (1994) Tetrahedron50:11827; Palucki et al. (1992) Tetrahedron Lett 33:7111; and Srinivasanet al. (1986) J Am Chem Soc 108:2309. Exemplary salenate ligandsdescribed in the above references are illustrated below, as well as inthe appended examples [Ph=phenyl; tBu=tert-butyl].

In yet another embodiment of the subject method, the tetradentatecatalyst of formula 100 is derived as a chiral tetradentate ligandrepresented, with the metal atom, by the general formula:

in which

-   -   D₁, D₂, D₃ and D₄ each represent heterocycles, such as pyrrole,        pyrrolidine, pyridine, piperidine, imidazole, pyrazine, or the        like;    -   each R₁₈ occurring in the structure represents a bridging        substituent which links adjacent heterocycles, and preferably        contains at least one stereogenic center of the ligand. For        example, each R₁₈, represents an alkyl, an alkenyl, an alkynyl,        or —R₁₅—R₁₆—R₁₇—, wherein R₁₅ and R₁₇ each independently are        absent or represent an alkyl, an alkenyl, or an alkynyl, and R₁₆        is absent or represents an amine, an imine, an amide, a        phosphonate, a phosphine, a carbonyl, a carboxyl, a silyl, an        oxygen, a sulfonyl, a sulfer, a selenium, or an ester;    -   each R₁₉, independently, is absent or represents one or more        substituents of the heterocycle to which it is attached, each        substituent independently selected from the group consisting of        halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl,        silyloxy, amino, nitro, thiol amines, imines, amides,        phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,        thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters,        and —(CH₂)_(m)—R₇;    -   or any two or more of the R₁₈ and R₁₉ substituents are        covalently linked to form a bridge substitution;    -   R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle;    -   m is zero or an integer in the range of 1 to 8; and    -   M represents a main-group metal,        wherein each of the substituents R₁₈ and R₁₉ are selected such        that the catalyst is asymmetric, e.g., the catalyst contains at        least one stereogenic center. The metal will generally be        coordinated with a counterion (as in the aged catalyst described        below).

In preferred embodiments, D₁-D₄ are substituted pyrroles, and thecatalyst is a chiral porphyrin or porphyrin-like ligand (hereinafter“porphyrinates”). As with the salenate ligands above, the synthesis of avast number of porphyrinates has been reported in the literature. Ingeneral, most chiral porphyrins have been prepared in three ways. Themost common approach involves attaching chiral units to preformedporphyrins such as amino- or hydroxy-substituted porphyrin derivatives(Groves et al. (1983) J Am Chem Soc 105:5791). Alternatively, chiralsubstituents can be introduced at the porphyrin-forming stage byallowing chiral aldehydes to condense with pyrrole (O'Malley et al.(1989) J Am Chem Soc 111:9116). Chiral porphyrins can also be preparedwithout the attachment of chiral groups. Similar to the bridgedenantiotopic faces described for the salenates above, bridgedporphyrinates can be generated by cross-linking adjacent and/or oppositepyrrolic positions and then separating the resulting mono-facedenantiomers with preparative HPLC using a chiral stationary phase(Konishi et al. (1992) J Am Chem Soc 114:1313). Ultimately, as with thegeneration of chiral salenate ligands, the resulting porphyrinate musthave no mirror plane in order to be considered chiral.

With reference to formula 100, it will be understood thatmetalloporphyrinate catalysts, in addition to being represented byformula 108, can be represented generally by the compound of formula 100when each of Z₁, Z₂, Z₃ and Z₄ represent nitrogen, and C₁ and C₂ alongwith their substituents (including R₁, R′₁, R₂, R₁₂) form foursubstituted pyrrole rings which include Z₁, Z₂, Z₃ and Z₄. To completethe square tetradentate ligand, each pyrrole ring is covalently attachedto the two adjacent pyrrole rings.

In preferred embodiments, the metalloporphyrinate catalyst isrepresented by the general formula 110:

in which

-   -   each R₂₀ occurring in structure 110, independently, represent        hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl,        alkoxyl, silyloxy, amino, nitro, thiolamines, imines, amides,        phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,        thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters,        or —(CH₂)_(m)—R₇;    -   each R₁₉ and R′₁₉ occurring in structure 110, independently,        represent hydrogen, halogens, alkyls, alkenyls, alkynyls,        hydroxyl, alkoxyl, silyloxy, amino, nitro, thiolamines, imines,        amides, phosphonates, phosphines, carbonyls, carboxyls, silyls,        ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes,        esters, or —(CH₂)_(m)—R₇;    -   or any two R₁₉ and R′₁₉ substituents on the same pyrrole can be        taken together to form a fused carbocycle or fused heterocycle        having from 4 to 7 atoms in the ring structure;    -   or any two or more of the R₁₉, R′₁₉ and R₂₀ substituents are        covalently cross-linked to form a bridging substituent;    -   R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle;    -   m is zero or an integer in the range of 1 to 8; and    -   M represents a main-group metal,        wherein the substituents R₁₉, R′₁₉ and R₂₀ are selected such        that the catalyst has at least one stereogenic center, e.g., is        asymmetric. The metal will generally be coordinated with a        counterion (as in the aged catalyst described below).

As with the salenate ligands previously described, it is possible tosterically and electronically “tune” the porphyrin ligands to optimizereaction yield and e.e. Examples of suitable porphyrin ligands andsynthesis schemes can be adapted from the art. For example, see Chang etal. (1979) J Am Chem Soc 101:3413; Groves et al. (1989) J Am Chem Soc111:8537; Groves et al. (1990) J Org Chem 55:3628; Mansuy et al. (1985)J Chem Soc Chem Commun p 155; Nauta et al. (1991) J Am Chem Soc113:6865; Collman et al. (1993) J Am Chem Soc 115:3834; and Kruper etal. (1995) J Org Chem 60:725.

Still another class of the tetradentate catalysts represented by thegeneral formula 100 and which are useful in the present asymmetricsynthesis reactions can be represented by the formula 112:

in which

-   -   each of the substituents R₁, R₂, R₃, R₄, R₅, R₁₁, R₁₂, R₁₃ and        R₁₄, independently, represent hydrogen, halogens, alkyls,        alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro,        thiolamines, imines, amides, phosphonates, phosphines,        carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,        selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇;        -   or any two or more of the substituents taken together form a            carbocycle or heterocycle having at least 4 atoms in the            ring structure;    -   R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle;    -   m is zero or an integer in the range of 1 to 8; and    -   M represents a main-group metal;        wherein    -   if R₅ is absent, at least one of R₁ and R₂ is covalently bonded        to at least one of R₃ and R₄, and    -   the substituents are selected such that the catalyst is        asymmetric. The metal will generally be coordinated with a        counterion (as in the aged catalyst described below).

Exemplary catalysts of formula 112 include:

Three Specific Formulations of 112

The synthesis of these and other related catalyst can be adapted fromthe literature. See, for example, Ozaki et al. (1990) J Chem Soc PerkinTrans 2:353; Collins et al. (1986) J Am Chem Soc 108:2088; and Brewer etal. (1988) J Am Chem Soc 110:423.

In yet another embodiment, the tetradentate catalysts of formula 100 canbe chosen from the class of azamacrocycle having a ligand represented bythe general formula 114:

wherein

-   -   R₂₁ and R₂₂ each represent hydrogen, halogens, alkyls, alkenyls,        alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro,        thiolamines, imines, amides, phosphonates, phosphines,        carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,        selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇;    -   R₂₀ is absent or represents one or more substituents of the        pyridine to which it is attached, each substituent independently        selected from the group consisting of halogens, alkyls,        alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro,        thiolamines, imines, amides, phosphonates, phosphines,        carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,        selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇;    -   R₂₃ and R₂₄ each independently are absent or represent one or        more substituents of the 1,3-diiminopropyl to which they are        attached, each substituent independently selected from the group        consisting of halogens, alkyls, alkenyls, alkynyls, hydroxyl,        alkoxyl, silyloxy, amino, nitro, thiolamines, imines, amides,        phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,        thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters,        or —(CH₂)_(m)—R₇;    -   or any two or more of the R₂₀, R₂₁, R₂₂, R₂₃ and R₂₄        substituents are covalently linked to form a bridging        substituent;    -   R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, a        heterocycle or a polycycle; and    -   m is zero or an integer in the range of 1 to 8,        wherein the substituents R₂₀, R₂₁, R₂₂, R₂₃ and R₂₄ are selected        such that the catalyst is asymmetric.

One advantage to this class of tetradentate catalysts, like thesalenates, derives from the fact that the ligand provides ametallo-shiff base complex. Furthermore, stereogenic centers can besited within two bond lengths of the metal center. Exemplary ligands offormula 114 include:

Two Specific Formulations of 114

The synthesis of these and other embodiments of 114 are described inPrince et al. (1974) Inorg Chim Acta 9:51-54, and references citedtherein.

Yet another class of tetradentate ligands of the subject method are thecyclams, such as represented by the general formula 116:

in which each of the substituents Q₈ indpendently, are absent orrepresent hydrogen or a lower alkyl, and each of R₂₅, R₂₆, R₂₇ and R₂₈,independently, represent one or more substituents on the ethyl or propyldiimine to which they are attached, which substituents are selected fromthe group of hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl,alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides,phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, and—(CH₂)_(m)—R₇; or any two or more of the substituents taken togetherform a bridging substituent; R₇ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; and m is zero or an integerin the range of 1 to 8. Wherein the substituents are selected such thatthe catalyst is asymmetric. Exemplary embodiments and synthesis schemesfor chiral cyclams useful in the present invention can be adapted fromthe art. See, for example, the Burrows et al. U.S. Pat. No. 5,126,464,Kimura et al. (1984) Inorg Chem 23:4181; Kimura et al. (1984) J Am ChemSoc 106: 5497; Kushi et al. (1985) J Chem Soc Chem Commun 216; Machidaet al. (1986) Inorg Chem 25:3461; Kimura et al. (1988) J Am Chem Soc110:3679; and Tabushi et al. (1977) Tetrahedron Lett 18:1049.B. Chiral Tridentate Catalysts

In yet another embodiment of the subject method, the chiral catalystwhich is provided in the reaction is from a class of chiral catalysthaving a tridentate ligand which coordinates a main-group metal in asubstantially planar geometry, though as above some distortion to thisgeometry is contemplated. Accordingly, this planar geometry refers totridentate ligands in which the Lewis basic atoms lie in the same plane,with the metal also in that plane, or slightly above or below thatplane.

Preferred planar tridentate catalysts which may be employed in thesubject reactions can be represented by the general formula 140:

wherein Z₁, Z₂, and Z₃ each represent a Lewis base, such as selectedfrom the group consisting of nitrogen, oxygen, phosphorus, arsenic andsulfur; the E₁ moiety, taken with Z₁, Z₂ and M, and the E₂ moiety, takenwith Z₂, Z₃ and M, each, independently, form heterocycles; R₈₀ and R₈₁each independently are absent, or represent one or more covalentsubstitutions of E₁ and E₂ with an organic or inorganic substituentpermitted by valence requirements of the ring atom to which it isattached, or any two or more of the R₈₀ and R₈₁ substituents takentogether form a bridging substituent; and M represents a main-groupmetal, wherein each R₁, R₂, R′₁, R′₂ R₈₀ and R₈₁ substituents areselected to provide at least one stereogenic center in said tridentateligand. In preferred embodiments, each R₈₀ and R₈₁ occuring in 140independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls,hydroxyl, alkoxyl, silyloxy, amino, nitro, thiolamines, imines, amides,phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₇; R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, aheterocycle or a polycycle; and m is zero or an integer in the range of1 to 8. The metal will generally be coordinated with a counterion (as inthe aged catalyst described below).

For example, a chiral tridentate catalyst useful in the subjectstereoselective reactions can have a ligand represented by the generalformula 142 and 144:

wherein each of R₁₀₀, R₁₀₂ and R₁₀₄ each independently are absent, orrepresent one or more covalent substitutions of heterocycle to which itis attached, or any two or more of the substituents taken together forma bridging substituent; wherein each R₁₀₀, R₁₀₂ and R₁₀₄ substituents,if present, can be selected from the group consisting of halogens,alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro,thiolamines, imines, amides, phosphonates, phosphines, carbonyls,carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones,aldehydes, esters, or —(CH₂)_(m)—R₇; R₇ represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. Again, the substitution of 142 isintended to provide at least one stereogenic center in the tridentateligand. Exemplary embodiments of the 2,2′:6′,2″-terpyridine ligands 142and their synthesis can be adapted from, for example, Potts et al.(1987) J Am Chem Soc 109:3961; Hadda et al. (1988) Polyhedron 7:575;Potts et al. (1985) Org Synth 66:189; and Constable et al. (1988) InorgChim Acta 141:201. Exemplary 2,6-bis(N-pyrazolyl)pyridine ligands 144can be adapted from, for example, Steel et al. (1983) Inorg Chem22:1488; and Jameson et al. (1990) J Org Chem 55:4992.

Yet another class of planar tridentate catalyst useful in the subjectstereoselective reactions can have a ligand represented by the generalformula 146:

wherein each of R₁₀₆, R₁₀₈ and R₁₁₀ can be selected from the groupconsisting of hydrogens, halogens, alkyls, alkenyls, alkynyls, hydroxyl,alkoxyl, silyloxy, amino, nitro, thiolamines, imines, amides,phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₇; R₁₁₂ is absent or represent one or more covalentsubstitutions of the heterocycle to which it is attached; or any two ormore of the R₁₀₆, R₁₀₈, R₁₁₀ and R₁₁₂ substituents taken together form abridging substituent; R₇ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. The choice of substitution of 146 is intended toenhance its chirality. Exemplary embodiments of thesalicylaldehyde-derived ligands 146 and their synthesis can be adaptedfrom, for example, Desimoni et al. (1992) Gazzetta Chimica Italiana122:269.

In a preferred embodiment, the tridentate ligand is given by the generalformula 150

-   -   wherein R₁₀₆ represents a hydrogen, halogen, alkyl, alkenyl,        alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiolamine,        imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl,        ether, thioether, sulfonyl, selenoether, ketone, aldehyde,        ester, or —(CH₂)_(m)—R₇; and each of R₁₁₂ and R′₁₁₂ is absent or        represent one or more covalent substitutions of the heterocycle        to which it is attached, such as designated for R₁₀₆; R₇        represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle        or a polycycle; and m is zero or an integer in the range of 1        to 8. For example, as described in the appended examples, a        preferred salicylaldehyde-derived ligand is given by the general        formula 152        each R₁₁₂ being independently selected.

Still another class of planar tridentate catalyst useful in the subjectstereoselective reactions can have a ligand represented by the generalformula 148:

wherein R₁₀₀ is as described above, and each R₁₁₆ and R₁₁₄ can beselected from the group consisting of hydrogens, halogens, alkyls,alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro,thiolamines, imines, amides, phosphonates, phosphines, carbonyls,carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones,aldehydes, esters, or —(CH₂)_(m)—R₇; or any two or more of thesubstituents taken together form a bridging substituent; R₇ representsan aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; andm is zero or an integer in the range of 1 to 8. The choice ofsubstitution of 148 is intended to provide at least one stereogeniccenter in the tridentate ligand. Exemplary embodiments of thesalicylaldehyde-derived ligands 148 and their synthesis can be adaptedfrom, for example, Marangoni et al. (1993) Polyhedron 12:1669.C. Tuning the Catalysts

The ligand substituents are chosen to optimize the selectivity of thereaction and the catalyst stability. The exact mechanism of action ofthe metallosalenate-catalyzed nucleophilic addition reactions has notyet been precisely elucidated. However, the need for stereoselectivenon-bonded interactions between the substrate and catalyst is a featureof this catalyst and other chiral planar catalysts of the subjectreaction. While not wishing to be bound by any particular theory, it isbelieved that the present nucleophilic addition reactions involve twofactors largely responsible for induction of asymmetry by formation ofstereospecific non-bonded pairs of catalyst and substrate, namely,steric and electronic interactions between a substrate and the ligand ofthe chiral catalyst. In general, “tuning” refers altering the stericbulk of the ligand to limit the approach of the substrate, utilizingsteric repulsions between the substrate and ligand substituents, andaltering the electronic characteristics of the ligand to influenceelectronic interactions between the substrate and the ligand, as well asthe rate and mechanism of the catalyzed reaction. For instance, thechoice of appropriate substituents as “blocking groups” enforces certainapproach geometries and disfavors others.

Furthermore, the choice of substituent may also affect catalyststability; in general, bulkier substituents are found to provide highercatalyst turnover numbers. It has been found that for the asymmetricepoxidation of olefins by Mn(salen) complexes, t-butyl groups (or othertertiary groups) are suitable bulky moieties for optimizingstereoselectivity and increasing catalyst turnover.

A preferred version of each of the embodiments described above providesa catalyst having a molecular weight less than 5,000 a.m.u., morepreferably less than 3,000 a.m.u., and even more preferably less than2,500 a.m.u. In another preferred embodiment, none of the substituentsof the core ligand, or any molecule coordinated to the metal in additionto the ligand, have molecular weights in excess 1,000 a.m.u., morepreferably they are less than 500 a.m.u., and even more preferably, areless than 250 a.m.u. The choice of substituent on the ligand can also beused to influence the solubility of the catalyst in a particular solventsystem.

As mentioned in brief above, the choice of ligand substituents can alsoaffect the electronic properties of the catalyst. Substitution of theligand with electron-rich (electron-donating) moieties (including, forexample, alkoxy or amino groups) increases the electron density of theligand and at the metal center. Conversely, electron-withdrawingmoieties (for example, chloro or trifluoromethyl) on the ligand resultin lower electron density of the ligand and metal center. The electrondensity of the ligand is important due to the possibility ofinteractions (such as π-stacking) with the substrate (see, e.g., Hamadaet al. Tetrahedron (1994) 50:11827). The electron density at the metalcenter may influence the Lewis acidity of the metal. Choice ofappropriate substituents thus makes possible the “tuning” of thereaction rate and the stereoselectivity of the reaction.

Substrates

Substrates which are useful in the present invention may be determinedby the skilled artisan according to several criteria. In general,suitable substrates will have one or more of the followingproperties: 1) The substrate will be capable of participating in anucleophilic addition reaction under the subject conditions; 2) Saidnucleophilic addition reaction will yield a useful product; 3) Thesubstrate will not react at undesired functionalities; 4) The substratewill react at least partly through a mechanism catalyzed by the chiralcatalyst; 5) The substrate will not undergo significant furtherundesired reaction after reacting in the desired sense; 6) The substratewill not substantially react with or degrade the catalyst, e.g. at arate greater than conversion of the substrate. It will be understoodthat while undesirable side reactions (such as catalyst degradation) mayoccur, the rates of such reactions can be manipulated through theselection of reactants and conditions; these manipulations will renderthe undesired side reaction(s) slow in comparison with the rate(s) ofthe desired reaction(s).

In certain embodiments, the reactive substrates may be contained in thesame molecule, thereby resulting in an intramolecular nucleophilicaddition reaction.

As discussed above, a wide variety of substrates are useful in themethods of the present invention. The choice of substrates will dependon factors such as the desired product, and the appropriate substrateswill be apparent to the skilled artisan. It will be understood that thesubstrates preferably will not contain any interfering functionalities.In general, appropriate substrates will contain a reactive π-bond and/ora nucleophilic locus.

Reaction Conditions

The asymmetric addition reactions of the present invention may beperformed under a wide range of conditions, though it will be understoodthat the solvents and temperature ranges recited herein are notlimitative and only correspond to a preferred mode of the process of theinvention.

In general, it will be desirable that reactions are run using mildconditions which will not adversely affect the substrate, the catalyst,or the product. For example, the reaction temperature influences thespeed of the reaction, as well as the stability of the reactants andcatalyst. The reactions will usually be run at temperatures in the rangeof −78° C. to 100° C., more preferably in the range −30° C. to 50° C.and still more preferably in the range −30° C. to 25° C.

In general, the asymmetric synthesis reactions of the present inventionare carried out in a liquid reaction medium. The reactions may be runwithout addition of solvent. Alternatively, the reactions may be run inan inert solvent, preferably one in which the reaction ingredients,including the catalyst, are substantially soluble. Suitable solventsinclude ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme,t-butyl methyl ether, tetrahydrofuran and the like; halogenated solventssuch as chloroform, dichloromethane, dichloroethane, chlorobenzene, andthe like; aliphatic or aromatic hydrocarbon solvents such as benzene,toluene, hexane, pentane and the like; esters and ketones such as ethylacetate, acetone, and 2-butanone; polar aprotic solvents such asacetonitrile, dimethylsulfoxide, dimethylformamide and the like; orcombinations of two or more solvents. Furthermore, in certainembodiments it may be advantageous to employ a solvent which is notinert to the substrate under the conditions employed. In certainembodiments, ethereal solvents are preferred.

The invention also contemplates reaction in a biphasic mixture ofsolvents, in an emulsion or suspension, or reaction in a lipid vesicleor bilayer. In certain embodiments, it may be preferred to perform thecatalyzed reactions in the solid phase.

In some preferred embodiments, the reaction may be carried out under anatmosphere of a reactive gas. The partial pressure of the reactive gasmay be from 0.1 to 1000 atmospheres, more preferably from 0.5 to 100atm, and most preferably from about 1 to about 10 atm. In certainembodiments it is preferable to perform the reactions under anatmosphere of an inert gas such as nitrogen or argon.

The asymmetric synthesis processes of the present invention can beconducted in continuous, semi-continuous or batch fashion and mayinvolve a liquid recycle and/or gas recycle operation as desired. Theprocesses of this invention are preferably conducted in batch fashion.Likewise, the manner or order of addition of the reaction ingredients,catalyst and solvent are also not critical and may be accomplished inany conventional fashion. In certain embodiments, particular orders ofcombination of substrate, nucleophile, catalyst, and solvent may resultin increased yield of product, increased stereo- or regio-selectivity,and/or increased reaction rate.

The subject reactions can be conducted in a single reaction zone or in aplurality of reaction zones, in series or in parallel or they may beconducted batchwise or continuously in an elongated tubular zone orseries of such zones. The materials of construction employed should beinert to the starting materials—substrate, nucleophile, catalyst, andsolvent—during the reaction and the fabrication of the equipment shouldbe able to withstand the reaction temperatures and pressures. Means tointroduce and/or adjust the quantity of starting materials oringredients introduced batchwise or continuously into the reaction zoneduring the course of the reaction can be conveniently utilized in theprocesses especially to maintain the desired molar ratio of the startingmaterials. The reaction steps may be effected by the incrementaladdition of one of the starting materials to the other. Also, thereaction steps can be combined by the joint addition of the startingmaterials to the optically active metal-ligand complex catalyst. Whencomplete conversion is not desired or not obtainable, the startingmaterials can be separated from the product and then recycled back intothe reaction zone.

The processes may be conducted in either glaas, glass-lined, stainlesssteel or similar type reaction equipment. The reaction zone may befitted with one or more internal and/or external heat exchanger(s) inorder to control undue temperature fluctuations, or to prevent anypossible “runaway” reaction temperatures.

Furthermore, the chiral catalyst can be immobilized or incorporated intoa polymer or other insoluble matrix by, for example, derivativation withone or more of substituents of the ligand. The immobilized ligands canbe complexed with the desired metal to form the chiral metallocatalyst.The catalyst, particularly the “aged” catalyst discussed herein, iseasily recovered after the reaction as, for instance, by filtration orcentrifugation.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1

This example describes the enantioselective addition of HCN to imines(the Strecker reaction) catalyzed by the chiral (salen)Al(III) complex8. In the first successful application of main-group (salen)metalcomplexes in asymmetric catalysis, excellent enantioselectivities areachieved in the hydrocyanation of a range of aryl substituted imines.The applicability of this methodology to the practical synthesis ofenantiomerically pure amino acid derivatives is illustrated in asynthesis of enantiopure (S)-2-naphthylglycine methyl ester on a 6 mmolscale.

The addition of cyanide to imines (the Strecker reaction)¹ constitutesone of the most direct and viable strategies for the asymmetricsynthesis of α-amino acid derivatives. Significant progress has beenmade in the development of stereoselective versions of this reactionusing imines bearing covalently attached chiral auxiliaries.² However,despite the obvious practical potential of an enantioselective catalyticversion of the Strecker reaction, only limited success has been attainedto this end.³ In this example, we describe the first example of a metalcatalyzed enantioselective Strecker reaction using a chiral(salen)Al(III) complex.

Chiral (salen)-metal complexes catalyze an array of asymmetricnucleophile-electrophile reactions including TMSN₃ ⁴ and carboxylic acidadditions to meso epoxides,⁵ hetero Diels-Alder,⁶ and TMSCN addition toaldehydes.⁷ Also, (salen)Cr and (salen)Co complexes have provenremarkably effective in the kinetic resolutions of terminal epoxideswith TMSN₃ ⁸ and H₂O.⁹ Encouraged by the proven effectiveness ofaldehydes and epoxides as electrophiles in (salen)-metal catalyzedenantioselective reactions, we evaluated the possibility of extendingthe scope of these catalysts to asymmetric transformations of imines. Tothis end, we screened a series of metal complexes of the readilyavailable salen ligand 1 for catalysis of the addition of TMSCN toN-allyl benzaldimine (9a). Complexes of Ti, Cr, Mn, Co, Ru and Al wereall found to catalyze the reaction at room temperature with varyingdegrees of conversion and enantioselectivity.¹⁰ The best result obtainedwas with the Al complex 8,^(11,12) which led to complete substrateconversion and afforded product 10a in 45% ee. Interestingly, noreaction was observed under strictly anhydrous conditions in thereaction catalyzed by 8, suggesting that the reacting species is HCNrather than TMSCN. At room temperature, the uncatalyzed reaction betweenHCN and 9a is quite rapid, but it is completely suppressed at −70° C. Atthis lower temperature, the reaction of 9a and HCN¹³ (1.2 equiv)catalyzed by 8 was complete within 15 h, and afforded 10a in 91%isolated yield and 95% ee (Table 1, entry a).^(14,15) TABLE 1

Entry R % yield^(a) % ee^(b) a 9a Ph 91 95 b 9b p-CH₃OC₆H₄ 93 91 c 9cp-CH₃C₆H₄ 99 94 d 9d p-ClC₆H₄ 92 81 e 9e p-BrC₆H₄ 93 79 f 9f 1-Naphthyl95 93 g 9g 2-Naphthyl 93(55)^(c) 93(>99)^(c) h 9h Cyclohexyl 77 57 i 9it-Butyl 69 37^(a)Isolated yield. Full Characeterization of compounds 10a-i isprovided in the Supporting Information.^(b)All ee's were determined by GC or HPLC chromatography usingcommercial chiral columns. See Supporting Information.^(c)After recrystallization from hexanes.

A variety of N-allyl imines were evaluated in the reaction catalyzed by8 (Table 1). The products 10a-i were isolated as the(S)-trifluoroacetamides in good yield and moderate-to-excellentenantioselectivity. Substituted aryl imines (9a-g) were clearly the bestsubstrates, affording very high levels of enantioselectivity (entriesa-g). In contrast, alkyl substituted imines underwent addition of HCNwith considerably lower ee's (entries h-i).

With the hope of improving the results obtainable with alkyl substitutedimines, we evaluated the effect of the catalyst structure and the iminenitrogen substituent on reaction enantioselectivity. Extensive variationof the steric and electronic properties of the (salen)AlCl ligandstructure failed to yield any improvement in reaction enantioselectivityover that obtained with catalyst 8. Several N-substituted imines ofpivalaldehyde, an attractive starting material for the asymmetricsynthesis of tert-leucine, were synthesized and screened (Table 2).Surprisingly, the N-substituent did not exert a very significantinfluence on the enantioselectivity of the reaction. Although only amarginal increase in ee was obtained with the N-benzyl derivative 11,enhancement of the enantiomeric purity to 97.5% was achievable withreasonably good recovery by recrystallization of the correspondingproduct 14. TABLE 2

P % yield % ee 10i Allyl 69 37 14 Benzyl 88(48)^(a) 49(97.5)^(a) 15p-methoxybenzyl 67 44 16 o-CH₃OC₆H₄ 74 40^(a)After recrystallization from 1:10 EtOAc:hexanes

The principal synthetic utility of the asymmetric Strecker reaction isfor the preparation of enantiomerically enriched α-amino acidderivatives. To illustrate the applicability of the present method,imine 9g was converted on 6 mmol scale to the amino methyl ester HClsalt 18, by means of a three step sequence requiring no chromatography(Scheme 1). With a reduced catalyst loading of 8 (2 mol %), thecorresponding amino nitrile was still obtained in high yield and in 92%ee within 15 h. Hydrolysis of the hydrocyanation adduct with methanolicHCl at reflux produced the allyl protected amino ester 17 in 78% yieldover two steps with no racemization. Deprotection was achieved byPd(0)-catalyzed deallylation using dimetylbarbituric acid as an allylscavenger¹⁶ followed by recrystallization to afford 18 in 60% yield andin enantiomerically pure form (>99% ee).

The asymmetric Strecker reaction catalyzed by 8 provides astraightforward entry into enantiomerically enriched α-amino acidderivatives using low catalyst loading from readily available substrateand catalyst precursors. The catalyst is easily prepared on large scaleand appears to have an indefinite “shelf life” even when stored underambient conditions. To our knowledge, this is the first instance inwhich a main group (salen)metal complex has been identified as a highlyeffective asymmetric catalyst. Experiments are underway to elucidate themechanism of this new enantioselective transformation, and to establishto what extent this reaction is related mechanistically to other classesof (salen)metal catalyzed nucleophile-electrophile reactions.¹⁷

REFERENCES AND NOTES

-   (1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.-   (2) (a) Williams, R. M. Synthesis of Optically Active α-Amino Acids;    Pergamon: Oxford, 1989, Chap. 5 and references cited therein. (b)    Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889-917. (c)    Duthaler, R. O. Tetrahedron 1994, 50, 1539.-   (3) (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J.    Am. Chem. Soc. 1996, 118, 4910. (b) Sigman, M. S.;    Jacobsen, E. N. J. Am. Chem. Soc., in press.-   (4) Martfnez, L. E.; Leighton, J. L.; Carsten, D. H.;    Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897.-   (5) Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J. F.;    Tokunaga, M. Tetrahedron Lett. 1997, 38, 773.-   (6) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,    63, 403.-   (7) (a) Belokon, Y.; Flego, M.; Ikonnikov, N.; Moscalenko, M.;    North, M.; Orizu, C.; Tararov, V.; Tasinazzo, M. J. Chem. Perkin    Trans. 1 1997, 1293. (b) Belokon, Y; Ikonikov, N.; Moscalenko, M.;    North, M.; Orlova, S.; Tararov, V.; Yashkina, L. Tetrahedron:    Asymmetry 1996, 7, 851.-   (8) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc.    1996, 118, 7420.-   (9) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.    Science 1997, 277, 936.-   (10) The corresponding vanadyl, Fe(III), Ni(II), Cu(II) and Sn(IV)    salen complexes were found to effect the reaction to less than 5%    conversion.-   (11) Catalyst Preparation (8): In a flamed dried 100 ml round bottom    flask equipped with a stir bar, 1.52 g (2.78 mmol) of (R,    R)-(−)—N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine    and 20 mL of CH₂Cl₂ (freshly distilled from CaH₂) were combined and    stirred. At ambient temperature, 1.54 ml of diethyl aluminum    chloride (1.8 M solution in toluene, 2.78 mmol) was added slowly to    the stirring solution. After stirring for 2 h, the solvents were    removed in vacuo and the resulting yellow solid was rinsed with 50    ml of hexanes. The solid was dried in vacuo to yield 8 (1.59 g, 95%    yield) as a yellow solid. mp>350° C. (dec); IR(KBr) 2966, 2953,    2867, 1640, 1544, 848 cm⁻¹; ¹H NMR (400 MHz, C₆D₆) δ 7.84 (s, 2H),    7.77 (s, 2H), 7.61 (s, 2H), 3.51 (m, 2H), 1.91 (s, 18H), 1.39 (s,    18H) 1.36 (m, 4H), 0.59 (m, 4H); ¹³C NMR {¹H} (100 MHz, CD₂Cl₂) δ    162.7, 141.2, 139.3, 131.4, 128.7, 128.4, 118.7, 64.6 (broad), 35.9,    34.4, 31.6, 30.0, 28.2, 24.1; Anal calcd. for C₃₆H₅₂AlClN₂O₂: C,    71.20; H, 8.42; Al, 4.44; Cl, 5.84; N, 4.61. Found: C, 71.05; H,    8.63; Al, 4.49; Cl, 5.73; N, 4.56.-   (12) For the synthesis of (salen)Al complexes see: (a) Dzugan, S.    J.; Goedken, V. L. Inorg. Chem. 1986, 25, 2858. (b) Gurian, P. L.;    Cheatham, L. K.; Ziller, J. W.; Barron, A. R. J. Chem Soc., Dalton    Trans. 1991, 1449. (c) Atwood, D. A.; Jegier, J. A.; Rutherford, D.    Inorg. Chem. 1996, 35, 63.-   (13) Ziegler, K. In Organic Synth. Coll. Vol. 1, Gilman, H.,    Blatt, A. H. Eds.; Wiley: New York, 1932; p. 314. CAUTION! Hydrogen    Cyanide is a highly toxic and volatile compound that should be    handled carefully to avoid inhalation.-   (14) The direct product of HCN addition was observed to undergo    racemization upon exposure to silica gel. The corresponding    triflouroacetamde derivatives were found to be stable, so all yield    and ee determinations were carried out on these derivatives.-   (15) Representative Procedure: Synthesis of Compound 10a. In a    flamed dried 5 mL round bottom flask equipped with a stir bar, 12 mg    of 8 (5 mol %, 0.02 mmol) and 1.4 mL of toluene were combined. The    reaction was stirred at ambient temperature until catalyst had    completely dissolved. The reaction flask was cooled to −70° C. by    means of a constant temperature bath and 1.2 equiv of HCN was added    (0.59 mmol, 690 μL of a 0.85 M solution in toluene). After 5 min, 71    mg (0.49 mmol) of 9a was added in one portion via syringe. After 15    h, the reaction was quenched with 103 μL of trifluoroacetic    anhydride (0.73 mmol, 1.5 equiv) and allowed to warm to ambient    temperature. The solvents were removed in vacuo and the resulting    residue was purified by flash chromatography (3:2 hexanes:CH₂Cl₂) to    afford 10a as a clear oil (119 mg, 91% yield).-   (16) Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993,    58, 6109.-   (17) Hanson, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem.    Soc. 1996, 44, 10924.

Supporting Information

General procedure: The same procedure as outlined for 10a in footnote 15of the main text of this example was followed for all compounds.

(10a): Product was obtained in 91% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 95% eeby Chiral GC analysis (γ-TA, 112° C., 23 min, 3° C./min to 123° C.,t_(r)(major) = 21.5 min, t_(r)(minor) = 23.9 min); [α]_(D) ²³ = 57.7° (c= 1.0, CH₂Cl₂); IR (thin film) 2936, 2249, 1701 cm⁻¹; ¹H NMR(400 MHz,CDCl₃)δ7.45(m, 5H), 6.65(s, 1H), 5.66(m, 1H), 5.19(d, J=10.2Hz, 1H),5.13(d, J=17.0Hz, 1H)4.15(dd, J=4.7, 17.0Hz, 1H), 3.91(dd, J=6.0,17.0Hz, 1H); ¹³C NMR {¹H} (100 MHz, CDCl₃)δ157.9(q, J=38Hz), 131.1,130.1, 130.0, 129.4, 127.8, 120.3, 117.5(q, J=288Hz), 115.2, 49.8, 48.6;HRMS m/z(M + NH₄ ⁺)calcd 286.1167, obsd 286.1163.

(10b): Product was obtained in 93% yield as a clear oil afterpurification by flash chromatography(3:2 hexanes:CH₂Cl₂) and in 91% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 ml./ min,t_(r)(major) = 9.7 min, t_(r)(minor) = 11.5 min; [α]_(D) ²³ = 56.1° (c =1.0, CH₂Cl₂); IR (thin film) 2940, 1701, 1613 cm^(−1;) ¹H NMR(400 MHz,CDCl₃)δ7.36(d, J=8.6Hz, 2H), 6.94(d, J=8.6Hz, 2H), 6.57(s, 1H), 5.65(m,1H), 5.19(d, J=10.2Hz, 1H), 5.14(d, J=17.2Hz, 1H), 4.15(dd, J=4.2,17.0Hz, 1H), 3.87(dd, J=6.2, 17.0Hz, 1H), 3.83(s, 3H); ¹³C NMR {¹H} (100MHz, CDCl₃) δ160.9, 157.8(q, J=38Hz), 131.4, 129.5, 121.9, 120.1,117.5(q, J=288Hz), 115.6, 114.8, 55.5, 49.4, 48.3; HRMS m/z (M⁺) calcd298.0929, obsd 298.0936.

(10c): Product was obtained in 99% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes: CH₂Cl₂) and in 94% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 ml./ min,t_(r)(major) = 5.5 min, t_(r)(minor) = 7.6 min); [α]_(D) ²³ = 42.4° (c =1.0, CH₂Cl₂); IR (thin film) 2930, 2249, 1703 cm⁻¹; ¹H NMR (400 MHz,CDCl₃)δ7.32(d, J=7.9Hz, 2H), 7.24(d, J=7.9Hz, 2H), 6.60(s, 1H), 5.68(m,1H), 5.20(d, J=10.2Hz, 1H), 5.14(d, J=17.2Hz, 1H), 4.14(dd, J=4.8,17.0Hz, 1H), 3.86(dd, J=6.5, 17.0Hz, 1H), 2.39(s, 3H);); ¹³C NMR {¹H}(100 MHz, CDCl₃)δ157.4(J=37Hz), 140.3, 131.2, 130.0, 127.8, 127.0,120.2, 117.4 (q, J=286Hz), 115.4, 49.5, 48.4, 21.1; HRMS m/z (M⁺) calcd282.0980, obsd 282.0981.

(10d) Product was obtianed in 92% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 81% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 ml./ min,t_(r)(major) = 5.9 min, t_(r)(minor) = 8.4min); [α]_(D) ²³ = 45.9° (c=1.0, CH₂Cl₂); IR (thin film) 2936, 1703 cm⁻¹; ¹H NMR(400 MHz,CDCl₃)δ7.40(m, 4H), 6.56(s, 1H), 5.65(m, 1H), 5.22(d, J=10.4Hz, 1H),5.17(d, J=17.2Hz, 1H), 4.16(dd, J=5.0, 17.0Hz, 1H), 3.94(dd, J=5.9,17.0Hz, 1H); ¹³C NMR {¹H } (100 MHz, CDCl₃)δ157.4(J=37Hz), 136.3, 130.9,129.6, 129.2, 128.8, 117.3(q, J=286Hz), 114.8, 49.4, 48.9; HRMS m/z (M⁺)calcd 302.0434, obsd 302.0448.

(10e): Product was obtained in 93% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 79% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 ml./min,t_(r)(major) = 6.2 min, t_(r)(minor) = 8.1 min); [α]_(D) ²³ = 48.0° (c =1.0, CH₂Cl₂); IR (thin film) 2936, 1701 cm⁻¹; ¹H NMR (400 MHz,CDCl₃)δ7.56(d, J=8.4Hz, 2H), 7.31(d, J=8.4Hz, 2H), 6.52(s, 1H), 5.65(m,1H), 5.21(d, J=10.2Hz, 1H), 5.15(d, J=17.1Hz, 1H), 4.15(dd, J=5.5,17.0Hz, 1H), 3.92(dd, J=6.3, 17.0Hz, 1H); ¹³C NMR {¹H} (100 MHz,CDCl₃)δ157.7, 132.7, 131.0, 129.5, 124.5, 120.8, 117.4, 114.8, 114.5,49.6, 49.0; HRMS m/z (M⁺) calcd 345.9929, obsd 345.9931.

(10f): Product was obtained in 95% yield as a white solid afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 93% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 ml./min,t_(r)(major) = 5.3 min, t_(r)(minor) = 10.0 min); [α]_(D) ²³ = 72.4° (c= 1.0, CH₂Cl₂); mp 92-95° C.; IR (KBr) 2920, 1697 cm⁻¹; ¹H NMR (400 MHz,CDCl₃)δ7.93(m, 3H), 7.55(m, 4H), 7.29(s, 1H), 5.46(m, 1H), 5.01(d,J=10.2Hz, 1H), 4.86(d, J=17.1Hz, 1H), 4.03(dd, J=4.3, 17.1Hz, 1H),3.50(dd, J=7.2, 17.1Hz, 1H); ¹³C NMR {¹H} (100 MHz,CDCl₃)δ157.4(J=37Hz), 133.6, 131.5, 131.0, 130.1, 129.3, 128.7, 128.0,126.9, 124.4, 121.3, 119.7, 117.4(q, J=286Hz), 115.9, 47.9, 47.3; HRMSm/z (M⁺) calcd 318.0980, obsd 318.0984.

(10g): Product was obtained in 93% yield as a white solid afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 93% eeby Chiral HPLC analysis (Chiralcel AS, 5% IPA/Hexanes, 1 ml./min,t_(r)(major) = 7.0 min, t_(r)(minor) = 8.4 min). Recrystallization froma minimal amount of hexanes at 0° C. yielded 54% (from imine) of thinneedles in >99% ee by HPLC analysis; [α]_(D) ²³ = 96.8° (c = 1.0,CH₂Cl₂); mp 72-73.° C.; IR (thin film) 3061, 2934, 1701 cm⁻¹; ¹H NMR(400 MHz, CDCl₃)δ8.06(s, 1H), 7.90(m, 3H), 7.59(m, 2H), 7.37(m, 1H)6.85(s, 1H), 5.69(m, 1H), 5.17(d, J=10.4Hz, 1H), 5.12(d, J=17.2Hz, 1H),4.20(dd, J=4.9, 17.0Hz, 1H), 3.50(dd, J=6.5, 17.0Hz, 1H); ¹³C NMR {¹H}(100 MHz, CDCl₃)δ157.9(q, J=38Hz), 133.6, 132.9, 131.2, 129.8, 128.3,128.1, 127.9, 127.7, 127.4, 124.2, 120.4, 117.6(q, J=287Hz), 115.4,114.7, 50.0, 48.6; HRMS m/z (M⁺) calcd 318.0980, obsd 318.0974.

(10h): Product was obtained in 77% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 57% eeby Chiral GC analysis (γ-TA, 120° C. isothermal, t_(r)(major) = 15.1min, t_(r)(minor) = 17.4 min); [α]_(D) ²³ = −10.4° (c = 1.0, CH₂Cl₂); IR(thin film) 2936, 2859, 1704 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ5.85(m, 1H),5.38(d, J=15.7Hz, 1H), 5.35(d, J=9.8Hz, 1H), 4.65(d, J=10.6Hz, 1H),4.26(dd, J=4.9, 16.9Hz, 1H)4.26(dd, J=6.9, 16.9Hz, 1H), 2.09(m, 2H),1.84-1.60(m, 4H), 1.40-0.85(m, 5H); ¹³C NMR {¹H} (100 MHz,CDCl₃)δ157.8(J=37Hz), 131.6, 120.6, 117.4(q, J=286Hz), 115.9, 53.6,50.4, 38.3, 30.0, 28.9, 25.7, 25.3, 25.1; HRMS m/z (M + NH₄ ⁺) calcd292.1637, obsd 292.1625.

(10i): Product was obtained in 69% yield as a clear oil afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 37% eeby Chiral GC analysis (γ-TA, 112° C. isothermal, t_(r)(major) = 4.4 min,t_(r)(minor) = 6.4 min); [α]_(D) ²³ = −20.4° (c = 1.0, CH₂Cl₂); IR (thinfilm) 2972, 1705 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ5.87(m, 1H), 5.33(d,J=10.4Hz, 1H), 5.25(d, J=17.2Hz, 1H), 4.25(s(br), 2H), 1.16(s, 9H); ¹³CNMR {¹H} (100 MHz, CDCl₃) δ157.5(J=37Hz), 132.0, 119.0, 117.4(q,J=286Hz), 115.3, 56.7, 40.5, 38.1, 26.9; HRMS m/z (M + NH₄ ⁺) calcd266.1480, obsd 266.1481.

(14): Product was obtained in 88% yield as a white solid afterpurification by flash chromatography (3:2 hexanes; CH₂Cl₂) and in 49% eeby Chiral GC analysis (γ-TA, 120° C. isothermal, t_(r)(major) = 26.4min, t_(r)(minor) = 28.4 min). Recrystallization from 1:10 EtOAc:hexanesyielded racemic crystals and the from the mother liquor 48% (from imine)of 97.5% ee by Chiral GC analysis; [α]_(D) ²³ = −56.2° (c = 1.0,CH₂Cl₂); mp 95-96° C.; IR (thin film) 2975, 2946, 1691 cm⁻¹; ¹H NMR (400MHz, CDCl₃)δ7.39(m, 3H), 7.19(m, 2H), 4.97(d, J=16.7Hz, 1H), 4.72(d,J=16.7Hz, 1H), 1.14(s, 9H); ¹³C NMR {¹H} (100 MHz, CDCl₃)δ157.4(J=37Hz),134.7, 129.1, 128.5, 126.3, 117.5(q, J=287Hz), 115.0, 57.6, 52.4, 38.6,27.3; HRMS m/z (M⁺) calcd 298.1293, obsd 298.1297.

(15): Product was obtained in 67% yield as a white solid afterpurification by flash chromatography (3:2 hexanes:CH₂Cl₂) and in 43% eeby Chiral GC analysi (γ-TA, 132° C. isothermal, t_(r)(major) = 57.9 min,t_(r)(minor) = 61.3 min); [α]_(D) ²³ = −28.7° (c = 1.0, CH₂Cl₂);108-109° C.; IR (thin film) 3014, 2976, 2942, 1696, 1518 cm⁻¹; ¹H NMR(400 MHz, CDCl₃)δ7.12(d, J=8.3Hz, 2H), 6.91(d, J=8.3Hz, 2H), 4.92(d,J=16.3Hz, 1H), 4.65(d, J=16.3Hz, 1H), 3.80(s, 3H), 1.13(s, 9H); ¹³C NMR{¹H} (100 MHz, CDCl₃)δ159.8, 157.3(J=37Hz), 127.9, 126.3, 117.6(q,J=287Hz), 115.0, 114.6, 57.4, 55.3, 52.1, 38.5, 27.3; ; HRMS m/z (M +Na)⁺ calcd 351.1296, obsd 351.1301.

(16): Product was obtained in 74% yield as a white solid afterpurification by flash chromatography (3:1 hexanes:CH₂Cl₂) and in 40% eeby Chiral HPLC analysis (as the trifluoroamide) (Chiralcel AS, 0.05% to1% IPA/Hexanes, 25 min, 1 ml./min, t_(r)(major) = 20.9min, t_(r)(minor)= 16.7 min); [α]_(D) ²³ = 54.2° (c = 1.0, CH₂Cl₂); IR (KBr) 3399, 2968,2940, 2911, 2230, 1602, 1511 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ6.92(m, 1H),6.83(m, 2H), 6.72(m, 1H), 4.47(d, J=10.1Hz, 1H), 3.96(d, J=10.1Hz, 1H),3.87(s, 3H), 1.21(s, 9H); ¹³C NMR {¹H} (100 MHz, CDCl₃)δ147.5, 135.4,121.3, 119.1, 119.0, 111.4, 110.1, 56.2, 55.7, 34.8, 26.2; HRMS m/z (M⁺)calcd 218.1419, obsd 218.1417. Synthesis of 18:

(17): To a flamed dried 100 ml round bottom flask, 1.17 g of 9h (6.00mmol), 73 mg 8 (0.12 mmol, 2 mol %), and 20 ml of freshly distilledtoluene were combined and stirred until homogeneous. The reaction wascooled to −78° C. and 8.5 ml of a solution of HCN in toluene (0.85 M,7.2 mmol, 1.2 equiv) was added by syringe addition. The mixture wasallowed to stir at −70° C. for 15 h followed by addition of anhydrousmethanolic HCl (3 ml). The solvents were removed in-vacuo and theresulting residue was dissolved in 25 ml of MeOH. The mixture was cooledto 0° C. and HCl gas was bubbled through until the reaction wassaturated. The solution was heated to reflux for 6 h, cooled and H₂O wasadded (3 ml). The solvents were removed in-vacuo and the resultingresidue was dissolved in 50 ml of H₂O and washed with hexanes (3 × 30ml). The aqueous layer was made alkaline by addition of saturated Na₂CO₃and extracted with CH₂Cl₂ (5 × 50 ml). The organic extracts were driedover Na₂SO₄ and the solvent was removed in-vacuo to yield 1.191 g (78%)of a clear oil.; IR (thin film) 1737 cm⁻¹; ¹H NMR (400 MHz,CDCl₃)δ7.82(m, 4H), 7.49(m, 3H), 5.91(ddt, J=17.2, 10.1, 7.1Hz, 1H),5.21(d, J=17.2Hz, 1H), 5.13(d, J=10.1Hz, 1H), 4.59(s, 1H), 3.70(s, 3H),3.24(d, J=7.1Hz, 2H), 2.11(s(br), 1H); ¹³C NMR {¹H} (100 MHz,CDCl₃)δ173.4, 136.0, 135.4, 133.3, 133.1, 128.5, 128.0, 127.7, 126.7,126.2, 126.1, 125.1, 116.7, 64.5, 52.3, 50.0; HRMS m/z (M⁺) calcd256.1338, obsd 256.1335.

(18): A solution of the allyl protected amino ester 17 (1.191 g, 4.67mmol) in 12 ml of degassed CH₂Cl₂ was added to a schlenk flaskcontaining 1.09 g of dimethylbarbataric acid (7.00 mmol, 1.5 equiv) and270 mg of Pd(PPh₃)₄ (0.23 mmol, 5 mol %). The reaction was allowed tostir for 2 hr followed by in-vacuo removal of solvent. The resultingmixture was dissolved in 50 ml of diethyl ether and washed withsaturated Na₂CO₃ (3 × 50 ml) and H₂O (2 × 50 ml). The organic layer wasthen extracted with 4 N HCl (4 × 50 ml) and the resulting aqueous layerwas washed with ethyl acetate (2 × 50 ml). The aqueous layer was thenfiltered to remove palladium salts and the resulting solids were washedwith methanol. The aqueous layer and methanol washes were combined andthe solvents removed in-vacuo. The resulting white powder was driedunder high vacuum to yield 1.109 g (94%) of the amine hydrochloridesalt. Recrystallization from MeOH:Et₂O (4:1) yielded product in 60% and99% ee by Chiral HPLC analysis as the trifluoroamide (Chiralcel AS, 5%IPA/Hexanes), 1 ml./min, t_(r)(minor) = 8.4 min, t_(r)(major) = 10.1min); [α]_(D) ²³ = 134.9° (c = 1.0, MeOH); IR (KBr) 2973, 2846, 1740cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆)δ9.29(s(broad), 3H)7.93(m, 4H), 7.59(m,3H), 5.43(s, 1H), 3.70(s, 3H); ¹³C NMR {¹H} (100 MHz, DMSO-d₆)δ168.8,133.0, 132.4, 130.0, 128.7, 128.0, 127.9, 127.7, 127.1, 126.9, 125.1,55.5, 53.1; HRMS m/z (M⁺) calcd 215.0946, obsd 215.0941.

Example 2 Preparation of(R,R)-1,2-Diphenyl-1,2-bis(3-tert-butylsalicylideamino)ethane

A solution of 360.5 mg (2.0 mmol) of 3-tert-butylsalicylaldehyde in 3 mlof EtOH was added dropwise to a solution of 212.3 mg (1.0 mmol) of(R,R)-1,2-diamino-1,2-diphenylethane in 5 ml of EtOH. The reactionmixture was heated to reflux for 1 h and water (5 ml) was added. The oilthat separated solidified upon standing. Recrystallization from MeOH/H₂Ogave 485.8 mg (91%) of yellow powder, mp 73-74° C. ¹H NMR (CDCl₃) δ 1.42(s, 18H, CH₃), 4.72 (s, 2H, CHN═C), 6.67-7.27 (m, 16H, ArH), 8.35 (s,2H, CH═N), 13.79 (s, 2H, ArOH) ppm; ¹³C NMR (CDCl₃) δ 29.3, 34.8, 80.1,117.8, 118.5, 127.5, 128.0, 128.3, 129.6, 130.1, 137.1, 139.5, 160.2,166.8 ppm. Anal. Calcd. for C₃₆H₄₀N₂O₂. C, 81.17; H, 7.57; N, 5.26.Found: C, 81.17; H, 7.60; N, 5.25.

Example 3 Preparation of(R,R)-1,2-Diphenyl-1,2-bis(3-diphenylmethylsilylsalicylideamino)ethane

3-(Diphenylmethylsilyl)salicylaldehyde was prepared from 2-bromophenolin 5 steps according to established procedures. A solution of 348.3 mg(1.09 mmol) of 3-(diphenylmethylsilyl)salicylaldehyde and 116.0 mg(0.546 mmol) of (R,R)-1,2-diamino-1,2-diphenylethane in 5 ml of ethanolwas heated to reflux for 0.5 h. A bright yellow oil separated from thesolution and it solidified upon standing. The mixture was filtered andthe yellow solid was washed with 2×5 ml ethanol. The isolated yield ofproduct pure by ¹H NMR analysis was 416 mg (97%). ¹H NMR (CDCl₃) δ 0.95(s, 3H), 4.68 (s, 2H), 6.72-7.55 (m, 36H, ArH), 8.37 (s, 2H), 13.34 (s,2H) ppm.

Example 4 Preparation of2,2′-Bis(3-tert-Butylsalicylideamino)-1,1′-Binaphthyl

A solution of 725 mg (4.0 mmol) of 3-tert-butyl-salicylaldehyde in 6 mlof EtOH was added dropwise to a solution of 569 mg (2.0 mmol) of(+)-2,2′-diamino-1,1-binaphthyl in 5 ml of EtOH. The reaction mixturewas heated to reflux for 8 h and then volatile materials were removedunder vacuum. The residue was purified by flash chromatography on 80 gSiO₂, using 20% CH₂Cl₂ in hexane as eluent. The mobile yellow fractionwas collected and solvents were removed under vacuum to give 725 mg(1.20 mmol, 59% yield) of the diimine as a yellow powder.

Example 5 Preparation of(S,S)-1,2,-bis(3,5-di-tert-butylsalicylide-amino)cyclohexane (2)

3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from theinexpensive, commercially available 2,4-di-t-butylphenol according toLarrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M.J Org Chem 1994, 59, 1939) was added as a solid to a 0.2 M solution of(S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co.,Milwaukee, Wis.) in absolute ethanol. The mixture was heated to refluxfor 1 hr. and then H₂O was added dropwise to the cooled bright yellowsolution. The resulting yellow crystalline solid was collected byfiltration and washed with a small portion of 95% ethanol. The yield ofanalytically pure salen ligand 2 obtained in this manner was 90-97%.

Spectroscopic and analytical data for the salen ligand: ¹H NMR (CDCl₃) δ13.72 (s, 1H), 8.30 (S, 1H), 7.30 (d, J=2.3 Hz, 1H), 6.98 (d, J=2.3 Hz,1H), 3.32 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.65 (m, 1H), 1.45 (m, 1H), 1.41(s, 9H), 1.24 (s, 9H). ¹³C NMR (CDCl₃): δ 165.8, 158.0, 139.8, 136.3,126.0, 117.8, 72.4, 34.9, 33.0, 31.4, 29.4, 24.3. Anal. Calcd. forC₃₆H₅₄N₂O₂: C, 79.07; H, 9.95; N, 5.12. Found: C, 79.12; H, 9.97; N,5.12.

Example 6 Synthesis of a Chiral Porphyrin Ligand

Pyrrole (1.0 equivalents) and salicylaldehyde (1.2 equivalents) aredissolved in propionic acid (1 liter/20 ml pyrrole) and the solution isrefluxed for 30 minutes. The reaction mixture is allowed to cool to roomtemperature and stand for one day. The mixture is filtered and theproduct is recrystallized to yield 5,10,15,20-tetrakis(2′-hydroxyphenyl)porphyrin.

The above-named porphyrin is dissolved in dimethylformamide, cooled to0° C., and treated with sodium hydride (4 equivalents). The mixture isstirred for 30 minutes, and then a solution of D-threitol 1,4-ditosylate(Aldrich Chemical Co.) in DMF is added slowly. When the addition isfinished, the reaction mixture is stirred for 30 minutes more, thencarefully quenched. The organic phase is washed with brine and thesolvent is evaporated. The residue is purified by HPLC to yield thechiral porphyrin.

Example 7 Enantioselective 1,4-Addition of Azide to N-Ethylmaleimide

A solution in toluene of N-ethylmaleimide, HN₃ (excess relative to themaleimide), and the (salen)AlN₃ catalyst depicted above (10 mol %relative to the maleimide) was maintained at −30° C. for 18 h. After astandard quench and work-up of the reaction mixture, the crude materialwas purified to yield 2-azido-N-ethylsuccinimide (93%, 93% ee).

All of the above-cited references and publications are herebyincorporated by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1-15. (canceled)
 16. A process of stereoselective chemical synthesiswhich comprises reacting a chiral or prochiral π-bond-containingsubstrate and a nucleophile in the presence of a chiral, non-racemiccatalyst to produce a stereoisomerically-enriched product, wherein saidπ-bond-containing substrate comprises a carbon-carbon orcarbon-heteroatom π-bond, said nucleophile comprises at least one pairof Lewis basic electrons, and said chiral, non-racemic catalystcomprises an asymmetric tridentate ligand complexed with a main-groupmetal atom.
 17. A stereoselective nucleophilic addition process whichcomprises: combining a chiral or prochiral π-bond-containing substrateand a nucleophile in the presence of a chiral, non-racemic catalyst toproduce a stereoisomerically enriched product, wherein saidπ-bond-containing substrate comprises at least one carbon-carbon orcarbon-heteroatom π-bond, said nucleophile comprises at least one pairof Lewis basic electrons, and said chiral, non-racemic catalystcomprises a tridentate chiral ligand having at least one Schiff basenitrogen complexed with a main-group metal; and maintaining thecombination under conditions appropriate for said chiral, non-racemiccatalyst to catalyze a stereoselective nucleophilic addition reactionbetween said chiral or prochiral π-bond-containing substrate and saidnucleophile.
 18. The process of claim 17, wherein the main-group metalis selected from Groups 1, 2, 12, 13, or 14 of the periodic table. 19.The process of claim 17, wherein the metal is a Group 12, 13, or 14main-group metal.
 20. The process of claim 17, wherein the metal atom isselected from the set comprising Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba,Zn, Cd, Hg, B, Al, Ga, In, Si, Ge, and Sn. 21-23. (canceled)
 24. Theprocess of claim 17, wherein the π-bond-containing substrate isrepresented by the general formula 1, the nucleophile is represented byNuY, and the product of the subject process is represented by 2: chiral,non-racemic catalyst

wherein R, R′, and R″ represent, independently for each occurrence,hydrogen, alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine,amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl,carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl,selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal,ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid,imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; X is selected from the group comprising CR₂, O, S, Se,and NR″; Y is selected, independently for each occurrence, from the setcomprising H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, SiR₃, and SnR₃;and Nu is selected from the set comprising conjugate bases of weakBronsted acids and carbanions; R₈₀ represents an unsubstituted orsubstituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or apolycycle; and m is an integer in the range 0 to 8 inclusive.
 25. Theprocess of claim 24, wherein R and R′ in 1 taken together form acarbocyclic or heterocyclic ring having from 4 to 8 atoms in the ringstructure.
 26. The process of claim 24, wherein R and R′ are chosen suchthat 1 does not have an internal plane of symmetry.
 27. The process ofclaim 17, wherein the π-bond-containing substrate is selected from thegroup comprising aldehydes, conjugated enals, thioaldehydes, conjugatedthioenals, selenoaldehydes, conjugated selenoenals, ketones, conjugatedenones, thioketones, conjugated thioenones, selenoketones, conjugatedselenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates,conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides,lactones, thionolactones, thiolactones, dithiolactones, lactams, andthiolactams; and the nucleophile is selected from the group comprisingconjugate bases of weak Bronsted acids and carbanions.
 28. The processof claim 17, which process is an enantioselective reaction.
 29. Theprocess of claim 17, which process is a diastereoselective reaction. 30.The process of claim 29, which diastereoselective reaction produces akinetic resolution.
 31. The process of claim 17, wherein the chiral,non-racemic catalyst has a molecular weight of less than 5,000 a.m.u.32-47. (canceled)
 48. A method for catalyzing a stereoselectivenucleophilic addition reaction which comprises: combining a chiral orprochiral π-bond-containing substrate and a nucleophile in the presenceof a chiral, non-racemic catalyst to produce a stereoisomericallyenriched product, wherein said π-bond-containing substrate comprises atleast one carbon-carbon or carbon-heteroatom π-bond, said nucleophilecomprises at least one pair of Lewis basic electrons, and said chiralcatalyst comprises a chiral tridentate ligand complexed with amain-group metal; and maintaining the combination under conditionsappropriate for said chiral, non-racemic catalyst to catalyze astereoselective nucleophilic addition reaction between saidπ-bond-containing substrate and said nucleophile.
 49. The method ofclaim 48, wherein the chiral tridentate ligand of the chiral catalyst isrepresented by the general formula:

in which Z₁, Z₂, and Z₃ each represent a Lewis base; the E₁ moiety,taken with Z₁, Z₂ and M, and the E₂ moiety, taken with Z₂, Z₃ and M,each, independently, form a heterocycle; R₈₀ and R₈, each independentlyare absent, hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl,alkoxyl, silyloxy, amino, nitro, thiolamines, imines, amides,phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₇, or any two or more of the R₈₀ and R₈₁ substituents takentogether form a bridging substituent; R₇ represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; m is zero oran integer in the range of 1 to 8; M represents a main-group metal; andA represents a counteranion or a nucleophile, wherein the tridentateligand is asymmetric. 50-61. (canceled)
 62. A method of realizing astereoselective addition of a nucleophile to a prochiral or chiralπ-bond-containing substrate, wherein the π-bond-containing substrate isrepresented by the general formula 1, and the nucleophile is representedby NuY, to give a product represented by 2:

wherein said chiral, non-racemic catalyst comprises a tridentate ligand;R, R′, and R″ represent, independently for each occurrence, hydrogen,alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide,phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide,anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl,ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl,heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide,oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or—(CH₂)_(m)—R₈₀; X is selected from the group comprising CR₂, O, S, Se,and NR″; Y is selected, independently for each occurrence, from the setcomprising H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, SiR₃, and SnR₃;and Nu is selected from the set comprising conjugate bases of weakBronsted acids and carbanions; R₈₀ represents an unsubstituted orsubstituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or apolycycle; and m is an integer in the range 0 to 8 inclusive; and whichmethod comprises reacting said π-bond-containing substrate with saidnucleophile in the presence of at least a catalytic amount of a chiralmetallosalenate catalyst.
 63. (canceled)
 64. (canceled)
 65. The methodof claim 62, wherein R, and R′ are chosen such that 1 does not have aninternal plane of symmetry.
 66. The method of claim 62, wherein theπ-bond-containing substrate is selected from the group comprisingaldehydes, conjugated enals, thioaldehydes, conjugated thioenals,selenoaldehydes, conjugated selenoenals, ketones, conjugated enones,thioketones, conjugated thioenones, selenoketones, conjugatedselenoenones, imines, oximes, hydrazones, glyoxylates, pyruvates,conjugated enoates, α,β-unsaturated amides, α,β-unsaturated imides,lactones, thionolactones, thiolactones, dithiolactones, lactams, andthiolactams; and the nucleophile is selected from the group comprisingconjugate bases of weak Bronsted acids and carbanions. 67-70. (canceled)71. The method of claim 62, which process is an enantioselectivereaction.
 72. The method of claim 62, which process is adiastereoselective reaction.
 73. The method of claim 72, whichdiastereoselective reaction produces a kinetic resolution. 74-77.(canceled)
 78. A method of providing a chiral, non-racemic α-aminonitrile, comprising reacting a prochiral or chiral imine with hydrogencyanide, or a surrogate thereof, in the presence of a chiral,non-racemic catalyst such that a chiral, non-racemic α-amino nitrile isformed, wherein the chiral, non-racemic catalyst comprises an asymmetrictridentate ligand complexed with a main-group metal atom, said complexhaving a planar or trigonal pyramidal geometry.
 79. The method of claim49, wherein the chiral, non-racemic tridentate ligand of the chiralcatalyst is represented by the general formula:

wherein R₁₀₆ represents a hydrogen, halogen, alkyl, alkenyl, alkynyl,hydroxyl, alkoxyl, silyloxy, amino, nitro, thiolamine, imine, amide,phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether,sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH₂)_(m)—R₇; eachof R₁₁₂ and R′₁₁₂ is absent or represent one or more covalentsubstitutions of the heterocycle to which it is attached; R₇ representsan aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; andm is zero or an integer in the range of 1 to 8.